Electrical stimulation devices for cancer treatment

ABSTRACT

Embodiments herein relate to a medical device for treating a cancerous tumor, the medical device having a first lead including a first wire and second wire; a second lead can include a third wire and fourth wire; and a first electrode in electrical communication with the first wire, a second electrode in electrical communication with the second wire, a third electrode in electrical communication with the third wire, and a fourth electrode in electrical communication with the fourth wire. The first and third electrodes form a supply electrode pair configured to deliver one or more electric fields to the cancerous tumor. The second and fourth electrodes form a sensing electrode pair configured to measure an impedance of the cancerous tumor independent of an impedance of the first electrode, the first wire, the third electrode, the third wire, and components in electrical communication therewith. Other embodiments are also included herein.

This application claims the benefit of U.S. Provisional Application No.62/837,125, filed Apr. 22, 2019, the content of which is hereinincorporated by reference in its entirety.

FIELD

Embodiments herein relate to electrical stimulation devices and methodsfor the treatment of cancer. More specifically, the embodiments relateto electrical stimulation leads and methods that can include featuresrelated to measuring one or more electrical properties, including butnot limited to impedance, capacitance, or voltage, at or near a site ofa cancerous tumor.

BACKGROUND

A living organism is made up of a complex three-dimensional architectureof biological tissue including cells and extracellular matrix surroundedby intracellular and extracellular fluids. The intracellular fluid foundinside of the cells of an organism is generally ionic, and includesvarious electrically active molecules such as ions, proteins,macronutrients, and nucleic acids. The extracellular fluid includesvarious fluids found outside of the cells of an organism. Examples ofextracellular fluids can include the blood plasma, lymph, cerebrospinalfluid, ocular fluid, synovial fluid, and saliva, to name a few. Theextracellular fluids are generally ionic in nature, and can includeelectrically active macronutrients such as ions, sugars, fatty acids,and metabolic waste products. The cell membranes of an organism includephospholipids and proteins, where the hydrophobic lipid tails aresandwiched between two layers of hydrophilic phosphate headgroups andvarious proteins associated therewith.

The biological tissue in a living organism has an electrical impedancewhen placed in an alternating electric field. The electrical impedanceof the biological tissue of a living organism can depend on the tissuetype, the health or diseased state of the tissue, and the frequency ofthe applied electric field. Electrical impedance of each type ofbiological tissue is determined by the cell type, intracellular fluid,and extracellular fluid composition for each specific tissue.

SUMMARY

In a first aspect, a medical device for treating a cancerous tumor isincluded. The medical device can include a first lead comprising a firstwire and a second wire; a second lead comprising a third wire and afourth wire; and a first electrode in electrical communication with thefirst wire, a second electrode in electrical communication with thesecond wire, a third electrode in electrical communication with thethird wire, and a fourth electrode in electrical communication with thefourth wire. The first electrode and the third electrode can form asupply electrode pair configured to deliver one or more electric fieldsat or near a site of the cancerous tumor. The second electrode and thefourth electrode can form a sensing electrode pair configured to measurean impedance of the cancerous tumor independent of an impedance of thefirst electrode, the first wire, the third electrode, the third wire,and components in electrical communication therewith.

In a second aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, the medicaldevice can include an electric field generating circuit configured togenerate the one or more electric fields.

In a third aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, the first leadand the second lead are each in electrical communication with theelectric field generating circuit.

In a fourth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, the medicaldevice can include a control circuitry in communication with theelectric field generating circuit, the control circuitry configured tocontrol delivery of the one or more electric fields from the electricfield generating circuit.

In a fifth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, where thecontrol circuitry can cause the electric field generating circuit togenerate one or more electric fields at frequencies selected from arange of between 10 kHz to 1 MHz at or near the site of the canceroustumor located within a bodily tissue.

In a sixth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, where themedical device can be configured to be implanted entirely within asubject.

In a seventh aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, where themedical device can be configured to be partially implanted within asubject.

In an eighth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, where the oneor more electric fields are delivered to the cancerous tumor atfrequencies selected from a range of from 100 kHz to 300 kHz.

In a ninth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, where acurrent flow through the second electrode, the second wire, the fourthelectrode, the fourth wire, and components in electrical communicationtherewith is less than 100 pA.

In a tenth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, where thefirst electrode and the second electrode of the first lead are spatiallyseparated along a longitudinal axis of the first lead by at least 1 mm;and wherein the third electrode and the fourth electrode of the secondlead are spatially separated along a longitudinal axis of the secondlead by at least 1 mm.

In an eleventh aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, wherein theone or more electric fields comprise an electric field strength selectedfrom a range of electric field strengths from 0.25 V/cm to 1000 V/cm.

In a twelfth aspect, a method for treating a cancerous tumor isincluded. The method can include implanting a first lead and a secondlead at or near a site of the cancerous tumor, where the first leadincludes a first wire and a second wire and the second lead includes athird wire and a fourth wire. The first wire can be in electricalcommunication with a first electrode; the second wire can be inelectrical communication with a second electrode; the third wire can bein electrical communication with a third electrode; and the fourth wirecan be in electrical communication with a fourth electrode. The firstelectrode and the third electrode can form a first supply electrode pairconfigured to deliver an electric field at or near a site of thecancerous tumor, and the second electrode and fourth electrode can forma first sensing electrode pair configured to measure impedance of thecancerous tumor independent of an impedance between the first sensingelectrode pair. The method can include applying a therapeutic electricfield at or near a site of the cancerous tumor using the first supplyelectrode pair for a predetermined period of time. The method caninclude measuring the impedance of the cancerous tumor using the firstsensing electrode pair.

In a thirteenth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, the method caninclude measuring an initial impedance of the cancerous tumor prior tobeginning treating the cancerous tumor, where measuring the initialimpedance includes applying a diagnostic electric field at or near thesite of the cancerous tumor and recording the initial impedance.

In a fourteenth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, wheremeasuring the impedance of the cancerous tumor includes obtainingmultiple measurements over a predetermined amount of time.

In a fifteenth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, the method caninclude determining a regression of the cancerous tumor by detecting anincrease in the impedance over the predetermined period of time.

In a sixteenth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, the method caninclude determining a progression of the cancerous tumor by detecting adecrease in the impedance over the predetermined period of time.

In a seventeenth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, the method caninclude adjusting the therapeutic electric field.

In an eighteenth aspect, a medical device for treating a cancerous tumoris included. The medical device can include an electric field generatingcircuit configured to generate one or more electric fields and controlcircuitry in communication with the electric field generating circuit,where the control circuitry is configured to control delivery of the oneor more electric fields from the electric field generating circuit. Thecontrol circuitry can cause the electric field generating circuit togenerate one or more electric fields at frequencies selected from arange of between 10 kHz to 1 MHz at or near a site of the canceroustumor. The medical device can include one or more supply leads inelectrical communication with the electric field generating circuit,where the one or more supply leads each include one or more supplyelectrodes in electrical communication with the electric fieldgenerating circuit. The medical device can include one or more sensingleads in electrical communication with the control circuitry, where theone or more sensing leads can each include one or more sensingelectrodes. The one or more sensing electrodes can be configured tomeasure an impedance of the one or more supply electrodes.

In a nineteenth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects. The medicaldevice can include a housing in which the electric field generatingcircuit and the control circuitry are disposed, where the housingincludes a portion that is in electrical communication with the electricfield generating circuit such that the housing serves as a supplyelectrode, and where the one or more electric fields are delivered alongat least one vector including a portion of the housing serving as asupply electrode.

In a twentieth aspect, in addition to one or more of the preceding orfollowing aspects, or in the alternative to some aspects, where the oneor more sensing electrodes are configured to perform unipolar impedancemeasurements to differentiate the impedance of each supply electrode.

This summary is an overview of some of the teachings of the presentapplication and is not intended to be an exclusive or exhaustivetreatment of the present subject matter. Further details are found inthe detailed description and appended claims. Other aspects will beapparent to persons skilled in the art upon reading and understandingthe following detailed description and viewing the drawings that form apart thereof, each of which is not to be taken in a limiting sense. Thescope herein is defined by the appended claims and their legalequivalents.

BRIEF DESCRIPTION OF THE FIGURES

Aspects may be more completely understood in connection with thefollowing drawings, in which:

FIG. 1 is a schematic circuit diagram in accordance with variousembodiments herein.

FIG. 2 is a schematic circuit diagram in accordance with variousembodiments herein.

FIG. 3 is a schematic view a medical device in accordance with variousembodiments herein.

FIG. 4 is a schematic view a medical device in accordance with variousembodiments herein.

FIG. 5 is a schematic view a medical device in accordance with variousembodiments herein.

FIG. 6 is a schematic view a medical device in accordance with variousembodiments herein.

FIG. 7 is a schematic view a medical device in accordance with variousembodiments herein.

FIG. 8 is a schematic view a medical device in accordance with variousembodiments herein.

FIG. 9 is a schematic view a medical device in accordance with variousembodiments herein.

FIG. 10 is a schematic cross-sectional view of a medical device inaccordance with various embodiments herein.

FIG. 11 is a schematic diagram of components of a medical device inaccordance with various embodiments herein.

FIG. 12 is a schematic view of a method in accordance with variousembodiments herein.

FIG. 13 is a schematic view of a method in accordance with variousembodiments herein.

FIG. 14 is a schematic view of a method in accordance with variousembodiments herein.

FIG. 15 is a schematic view of a method in accordance with variousembodiments herein.

FIG. 16 is a plot of an exemplary electric field in accordance withvarious embodiments herein.

FIG. 17 is a plot of an exemplary electric field in accordance withvarious embodiments herein.

While embodiments are susceptible to various modifications andalternative forms, specifics thereof have been shown by way of exampleand drawings, and will be described in detail. It should be understood,however, that the scope herein is not limited to the particularembodiments described. On the contrary, the intention is to covermodifications, equivalents, and alternatives falling within the spiritand scope herein.

DETAILED DESCRIPTION

As discussed above, the biological tissue in a living organism has anelectrical impedance when placed in an alternating electric field. Likeany healthy tissue, a cancerous tumor, including at least one cancerouscell population, can also exhibit an electrical impedance influenced byits cell type, intracellular fluid, and extracellular fluid associatedtherewith, when placed in an electric field. However, the impedance ofcancerous tissue can vary in comparison to healthy tissue. Further, theimpedance of cancerous tissue can vary as a result of treatment of thecancerous tissue. As such, measuring and monitoring the impedance oftissue before, during and after treatment (regardless of treatmentmodality) can provide valuable clinical insights in order to guidefurther therapy. In addition, the impedance of device componentsthemselves (including, but not limited to, electrodes, leads, andcomponents in electrical communication therewith) before, during andafter treatment (regardless of treatment modality) can provide valuableclinical insights in order to guide further therapy.

Impedance can be measured within a biological tissue using a number ofmethods, including a two-wire impedance measurement or a four-wireimpedance measurement. Referring now to FIG. 1, a two-wire circuitdiagram 100 for measuring impedance within a biological tissue is shownin accordance with the embodiments herein. The two-wire circuit diagram100 includes a first wire 102 having a first wire resistance 104 and afirst electrode 106 in electrical communication with first wire 102. Thetwo-wire circuit diagram 100 also includes a second wire 114 having asecond wire resistance 112 and a second electrode 110 in electricalcommunication with second wire 114. The first electrode 106 and thesecond electrode 110 are placed in close proximity to a tissue 108 to betreated. By way of example, the tissue 108 to be treated can include ahealthy bodily tissue or a diseased bodily tissue, such as a canceroustumor.

The two-wire circuit diagram 100 also includes a current source 116 anda voltmeter 118. The direction of the current flow through the circuitis depicted by current flow arrows 120 and 122. The first electrode 106and the second electrode 110 are each configured to perform thefunctions of supplying an electric field at or near the site of thetissue 108 to be treated and to sense an impedance at or near the siteof the tissue 108 to be treated. Thus, in this scenario, a known currentis supplied to the tissue 108 and the voltage drop is measured using thesame electrode pair (or electrical potential difference between the twoelectrodes of the electrode pair). Impedance can then be calculatedaccording to Ohm's law (V=IR or V=IZ). However, when measured in thismanner, the current through the circuit experiences a voltage dropacross first wire resistance 104 and second wire resistance 112. Thecurrent flow through the circuit can experiences a voltage drop due toimpedance within the wires, the electrodes, and any other components inelectrical communication therewith. Thus, the voltage 124 measured byvoltmeter 118 across the tissue 108 will include interference from thevoltage drop within the components of the two-wire circuit 100 and willbe different than the actual voltage drop 126 across tissue 108. Assuch, any impedance as measured through the tissue 108 will also includeimpedance of components of the two-wire circuit 100. While not intendingto be bound by theory, it is believed that this interference withmeasuring the impedance of the tissue 108 can be detrimental to theclinical value of measurement and/or monitoring of tissue 108 impedanceand make it less valuable for guiding therapy.

A four-wire system for measuring impedance can offer enhanced accuracyand specifically can reduce or eliminate the interference to theimpedance measurement associated with a two-wire system. Referring nowto FIG. 2, an exemplary four-wire circuit diagram 200 for measuringimpedance within a biological tissue is shown in accordance with theembodiments herein. The four-wire circuit diagram 200 differs from thetwo-wire circuit diagram in that the four-wire circuit diagram includesseparate supply electrodes and separate sensing electrodes. Thefour-wire circuit diagram 200 includes a first wire 202 having a firstwire resistance 204 and a first supply electrode 206 in electricalcommunication with first wire 202. The four-wire circuit diagram 200also includes a second wire 214 having a second wire resistance 212 anda second supply electrode 210 in electrical communication with secondwire 214. The first supply electrode 206 and the second supply electrode210 are placed in close proximity to a tissue 108 to be treated. By wayof example, the tissue 108 to be treated can include a healthy bodilytissue or a diseased bodily tissue, such as a cancerous tumor. The firstsupply electrode 206 and the second supply electrode 210 are configuredto supply one or more electric fields at or near the site of the tissue108.

The four-wire circuit diagram 200 further includes a third wire 224having a third wire resistance 226 and a first sensing electrode 228 inelectrical communication with third wire 224. The four-wire circuitdiagram 200 also includes a fourth wire 234 having a fourth wireresistance 232 and a second sensing electrode 230 in electricalcommunication with fourth wire 234. The first sensing electrode 228 andthe second sensing electrode 230 are placed in close proximity to atissue 108 to be treated, and they are configured to measure animpedance within the tissue 108.

The four-wire circuit diagram 200 also includes a current source 116 anda voltmeter 118. The direction of the current flow through the circuitis depicted by current flow arrows 220 and 222. The current isconfigured to flow through the first supply electrode 206, the tissue108, and the second supply electrode 210, and any wires and componentsin electrical communication therewith. In contrast to the two-wirecircuit 100, the four-wire circuit 200 is configured such thatnegligible current flows through the sensing electrodes and the wiresand components in electrical communication therewith. As such, thevoltage 236 measured by the voltmeter 118 is substantially identical tothe voltage 238 across the tissue 108. Any impedance within the firstwire, the first supply electrode, the second wire, the second supplyelectrode, and any components in electrical communication therewith willnot be measured along with the impedance sensed across the tissue 108alone.

The impedance of a cancerous tumor can be measured using any of themedical devices described herein and can be done using a two-wire,four-wire, or other system. Referring now to FIG. 3 and FIG. 4,schematic diagrams of a subject 301 with a cancerous tumor 310 are shownin accordance to the embodiments herein. In FIG. 3, the subject 301 hasa medical device 300 implanted entirely within the body of the subject301 at or near the site of cancerous tumor 310. Various implant sitescan be used including areas such as in the limbs, the upper torso, theabdominal area, the head, and the like. In FIG. 4, the subject 301 has amedical device 400 at least partially implanted within body of thesubject 301 at or near the site of a cancerous tumor. In someembodiments, the medical device can be entirely external to the subject.In some embodiments, the medical device can be partially external to thesubject. In some embodiments, the medical device can be partiallyimplanted and partially external to the body of a subject. In otherembodiments, a partially implanted medical device can include atranscutaneous connection between components disposed internal to thebody and external to the body. A partially or fully implanted medicaldevice can wirelessly communicate with a partially or fully externalportion of a medical device over a wireless connection.

In some embodiments, a portion of the medical device can be entirelyimplanted and a portion of the medical device can be entirely external.For example, in some embodiments, one or more electrodes or leads can beentirely implanted within the body, whereas the portion of the medicaldevice that generates an electric field, such as an electric fieldgenerator, can be entirely external to the body. It will be appreciatedthat in some embodiments described herein, the electric field generatorsdescribed can include the many of the same components as and can beconfigured to perform many of the same functions as a pulse generator.In embodiments where a portion of a medical device is entirelyimplanted, and a portion of the medical device is entirely external, theportion of the medical device that is entirely external can communicatewirelessly with the portion of the medical device that is entirelyinternal. However, in other embodiments a wired connection can be used.

The medical device 300 can include a housing 302 and a header 304coupled to the housing 302, and medical device 400 can include a housing302. Various materials can be used. However, in some embodiments, thehousing 302 can be formed of a material such as a metal, ceramic,polymer, composite, or the like. In some embodiments, the housing 302,or one or more portions thereof, can be formed of titanium. The header304 can be formed of various materials, but in some embodiments theheader 304 can be formed of a translucent polymer such as an epoxymaterial. In some embodiments the header 304 can be hollow. In otherembodiments the header 304 can be filled with components and/orstructural materials such as epoxy or another material such that it isnon-hollow.

In some embodiments where a portion of the medical device 300 or 400 ispartially external, the header 304 and housing 302 can be surrounded bya protective casing made of durable polymeric material. In otherembodiments, where a portion of the medical device 300 or 400 ispartially external, the header 304 and housing 302 can be surrounded bya protective casing made of a combination of polymeric material,metallic material, and/or glass material.

Header 304 can be coupled to one or more leads, such as leads 306. Theheader 304 can serve to provide fixation of the proximal end of one ormore leads 306 and electrically couple the one or more leads 306 to oneor more components within the housing 302. The one or more leads 306 caninclude one or more electrodes, such as electrodes 308, disposed alongthe length of the leads 306. In some embodiments, electrodes 308 caninclude electric field generating electrodes, also referred to herein as“supply electrodes,” and in other embodiments electrodes 308 can includeelectric field sensing electrodes. In some embodiments, leads 306 caninclude both electric field generating and electric field sensingelectrodes. In other embodiments, leads 306 can include any number ofelectrodes that are both electric field sensing and electric fieldgenerating. It will be appreciated that while many embodiments ofmedical devices herein are designed to function with leads, leadlessmedical devices that generate electrical fields are also contemplatedherein. In some embodiments, the electrodes 308 can be tip electrodes onthe most distal end of the leads 306.

It will be appreciated that components within a medical device,including leads, electrodes, and any components in electricalcommunication with any of the forgoing that form part of an electricalcircuit can produce an impedance within the medical device. A medicaldevice having four wires and four electrodes can be configured tomeasure impedance within a cancerous tumor and can separate theimpedance of the medical device components from the impedance across thecancerous tumor, thus allowing a more accurate measurement of impedanceassociate with the cancerous tumor itself. Referring now to FIG. 5, amedical device 500 for treating a cancerous tumor 310 is shown inaccordance with the embodiments herein. The medical device 500 caninclude a first lead 502 comprising a first wire 504 (shown as a solidline) and a second wire 506 (shown as a dashed line). The medical device500 can include a second lead 508 comprising a third wire 510 (shown asa solid line) and a fourth wire 512 (shown as a dashed line). The firstwire 504 and the third wire 510 can be configured as supply wires forsupplying an electric field at or near the site of the cancerous tumor.The second wire 506 and the fourth wire 512 can be configured as sensingwires for measuring an impedance at or near the site of the canceroustumor.

The first lead 502 of medical device 500 can include a first electrode514 in electrical communication with the first wire 504 and a secondelectrode 516 in electrical communication with the second wire 506. Thesecond lead 508 of medical device 500 can include a third electrode 518in electrical communication with the third wire 510 and a fourthelectrode 520 in electrical communication with the fourth wire 512. Thefirst electrode 514 and the third electrode 518 can be configured assupply electrodes to form a supply electrode pair that can deliver anelectric field 522 at or near a site of the cancerous tumor 310. Thesecond electrode 516 and the fourth electrode 520 can be configured aselectric field sensing electrodes to form a sensing electrode pairconfigured to measure an impedance 524 of the cancerous tumor 310, whereimpedance 524 is independent of an impedance of any circuit formed bythe first electrode 514, the first wire 504, the third electrode 518,the third wire 510, and any components in electrical communicationtherewith.

In some embodiments, if two or more electrodes are present on the leadsof the medical devices herein, each electrode can be spatially separatedalong a longitudinal axis of the lead by at least 0.1, 0.2, 0.25, 0.3,0.35, 0.4, 0.5, 0.75, 1, 2, 3, 4, 5, or 10 cm (or by an amount fallingwithin a range between any of the foregoing). By way of example, thefirst electrode 514 and the 516 second electrode of the first lead 502are spatially separated along a longitudinal axis of the first lead 502by at least 1 mm; and the third electrode 518 and the fourth electrode520 of the second lead 508 are spatially separated along a longitudinalaxis of the second lead 508 by at least 1 mm.

In some embodiments, the electrodes described herein can be spatiallyseparated along a longitudinal axis of the leads described herein by adistance that can be greater than or equal 1 mm, 5 mm, 10 mm, 15 mm, 20mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, or 100 mm, 150 mm, 200 mm, or 250mm. In some embodiments, the electrodes herein can be spatiallyseparated in more than one dimension from neighboring electrodes by adistance that can be greater than or equal 1 mm, 5 mm, 10 mm, 15 mm, 20mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, or 100 mm, 150 mm, 200 mm, or 250mm.

It will be appreciated that the current flow through the first electrode514 and third electrode 518 will not appreciably pass through thesensing electrode pair, including the second electrode 516 and fourthelectrode 520. Thus, the current flow through the second electrode 516,the second wire 506, the fourth electrode 520, the fourth wire 512, andcomponents in electrical communication therewith is negligible. In someembodiments, the current flow through the second electrode 516, thesecond wire 506, the fourth electrode 520, the fourth wire 512, andcomponents in electrical communication therewith is less than 2000,1000, 750, 500, 250, 100, 50, or 10 pA.

In some embodiments, the four wires of the medical devices herein caneach be present in separate leads, spatially separate from one another.Referring now to FIG. 6, medical device 600 for treating a canceroustumor 310 is shown in accordance with the embodiments herein. Themedical device 600 can include a first lead 602 comprising a first wire604, a second lead 606 comprising a second wire 608, a third lead 610comprising a third wire 612, and a fourth lead 614 comprising a fourthwire 616. The first wire 604 and the third wire 612 can be configured assupply wires for supplying an electric field at or near the site of thecancerous tumor. The second wire 608 and the fourth wire 616 can beconfigured as sensing wires for measuring an impedance at or near thesite of the cancerous tumor.

The first lead 602 can include a first electrode 618 in electricalcommunication with the first wire 604. The second lead 606 can include asecond electrode 620 in electrical communication with the second wire608. The third lead 610 can include a third electrode 622 in electricalcommunication with the third wire 612. The fourth lead 614 can include afourth electrode 624 in electrical communication with the fourth wire616. The first electrode 618 and the third electrode 622 can beconfigured as supply electrodes to form a supply electrode pairconfigured to deliver an electric field at or near a site of thecancerous tumor 310. The second electrode 620 and the fourth electrode624 can be configured as sensing electrodes to form a sensing electrodepair configured to measure impedance 524 of the cancerous tumor 310,where the impedance 524 is independent of an impedance of the firstelectrode 618, the first wire 604, the third electrode 622, the thirdwire 612, and any components in electrical communication therewith. Insome embodiments, the first wire, the second wire, the third wire, thefourth wire, etc., can be electrically insulated from one another. Inother embodiments, more than four leads and/or more than four wires canbe utilized.

The first electrode 618 and the third electrode 622 that form the supplyelectrode pair can deliver an electric field along a first vector at ornear the site of a cancerous tumor, and the second electrode 620 and thefourth electrode 624 that form the sensing electrode pair can measureimpedance 524 of the cancerous tumor along a second vector at or nearthe site of the cancerous tumor. The first vector and second vector canbe spatially and or directionally separate from one another. In someembodiments, the first vector and second vector can be spatially and ordirectionally separated (e.g., the vectors can be disposed at an anglewith respect to one another) by at least about 10, 20, 30, 40, 50, 60,70, 80 or 90 degrees. It will be appreciated that the supply electrodepair can deliver an electric field at or near the site of a canceroustumor along multiple vectors, and that the sensing electrode pair cansimilarly measure impedance along multiple vectors that are spatiallyseparate from the vector used to deliver the electric field. In someembodiments, the sensing electrodes can be configured to sense animpedance 524 within a cancerous tumor along one or more vectors thatare non-therapy vectors.

The medical devices herein can include additional configurations usingmore than one set of four wires to measure impedance at or near the siteof a cancerous tumor. For example, the medical devices herein caninclude two sets of four wires to measure impedance within a canceroustumor. Referring now to FIG. 7, medical device 700 for treating acancerous tumor 310 is shown in accordance with the embodiments herein.Medical device 700 includes a first lead 602, a second lead 606, a thirdlead 610, and a fourth lead 614. The first lead 602 can include a firstelectrode 618 and a fifth electrode 702. The second lead 606 can includea second electrode 620 and a sixth electrode 704. The third lead 610 caninclude a third electrode 622 and a seventh electrode 706. The fourthlead 614 can include a fourth electrode 624 and an eighth electrode 708.It will be appreciated that, while not shown, the fifth electrode is inelectrical communication with a fifth wire, the sixth electrode is inelectrical communication with a sixth wire, the seventh electrode is inelectrical communication with a seventh wire, and the eighth electrodeis in electrical communication with an eighth wire. Each of the wireswithin each respective lead can be electrically insulated from eachother.

The first electrode 618 and the third electrode 622 can be configured assupply electrodes that form a first supply electrode pair configured todeliver an electric field at or near a site of the cancerous tumor 310.The second electrode 620 and the fourth electrode 624 can be configuredas sensing electrodes that form a first sensing electrode pairconfigured to measure an impedance 524 of the cancerous tumor 310, whereimpedance 524 is independent of an impedance of the first electrode 618,the third electrode 622, and any wires and any components in electricalcommunication therewith. The fifth electrode 702 and the seventhelectrode 706 can be configured as supply electrodes that form a secondsupply electrode pair configured to deliver an electric field at or neara site of the cancerous tumor 310. The sixth electrode 704 and theeighth electrode 708 can be configured as sensing electrodes that form asecond sensing electrode pair configured to measure an impedance 524 ofthe cancerous tumor 310, where impedance 524 is independent of animpedance of the fifth electrode 702, seventh electrode 706, and anywires and any components in electrical communication therewith.

The first electrode 618 and the third electrode 622 that form the firstsupply electrode pair can deliver an electric field along a first vectorat or near the site of a cancerous tumor, and the second electrode 620and the fourth electrode 624 that form the first sensing electrode paircan measure an impedance 524 along a second vector at or near the siteof a cancerous tumor. The fifth electrode 702 and the seventh electrode706 that form the second supply electrode pair can deliver an electricfield along a third vector at or near the site of a cancerous tumor, andthe sixth electrode 704 and the eighth electrode 708 that form thesecond sensing electrode pair can measure an impedance 524 along afourth vector at or near the site of a cancerous tumor.

The electric field can be delivered by the first supply electrode pairat or near the site of a cancerous tumor along a first vector, while thefirst sensing electrode pair can sense impedance along a second vectorthat is spatially and/or directionally separate from the first vector.In some embodiments, the first vector and second vector can be spatiallyand/or directionally separated (e.g., the vectors can be disposed at anangle with respect to one another) by at least about 10, 20, 30, 40, 50,60, 70, 80 or 90 degrees. Similarly, the electric field can be deliveredby the second supply electrode pair at or near the site of a canceroustumor along a third vector, while the second sensing electrode pair cansense impedance along a fourth vector that is spatially separate fromthe third vector. In some embodiments, the third vector and fourthvector can be spatially and/or directionally separated (e.g., thevectors can be disposed at an angle with respect to one another) by atleast about 10, 20, 30, 40, 50, 60, 70, 80 or 90 degrees. It will beappreciated that the first or second supply electrode pairs can deliveran electric field at or near the site of a cancerous tumor alongmultiple vectors, and that the first or second sensing electrode pairscan similarly measure impedance along multiple vectors that arespatially and/or directionally separate from the vector used to deliverthe electric field.

It will be appreciated that while the first and second supply electrodepairs of medical device 700 are disposed across the first lead 602 andthird lead 610, and the first and second sensing electrode pairs arefound disposed across the second lead 606 and fourth lead 614, anyconfiguration of electrode pairs can be implemented on the leads of themedical devices herein. By way of example, in FIG. 7, first lead 602 andthird lead 610 can each include a first supply electrode pair and afirst sensing electrode pair, and second lead 606 and fourth lead 614can also include a first supply electrode pair and a first sensingelectrode pair.

In some embodiments herein, the medical devices can include bothinternal and external components. Referring now to FIG. 8, a schematicdiagram of a medical device 800 is shown in accordance with theembodiments herein. Medical device 800 can include an internal portionat the internal side 850 of the subject's body and an external portionat the external side 852 of the subject's body. The internal portion ofmedical device 800 can include internal electric lead 801 and theexternal portion can include the housing 302 and the external electriclead 802. The medical device 800 can also include a transcutaneousaccess port 820 spanning the exterior surface 822 of the subjects bodyat or near the site of the cancerous tumor suitable to receive one ormore leads or catheters. By way of example, transcutaneous access port820 can be configured to receive at least one of the internal electriclead 801, a drug delivery catheter for delivery of one or morechemotherapeutic agents, an optical lead comprising one or more opticalemitters for delivering optical energy, a biopsy apparatus for obtaininga biopsy sample from the cancerous tumor, or an irrigation catheter forflushing the site of the cancerous tumor of waste products or bodilyfluids.

Internal electric lead 801 can include one or more electrodes such assensing electrodes 804 and 808, and supply electrodes 806 and 810disposed along the length of internal electric lead 801. Externalelectric lead 802 can include sensing electrodes 812 and 816, and supplyelectrodes 814 and 818 disposed along the length of the externalelectric lead 802. In some embodiments, electrodes 804, 806, 808, 810,812, 814, 816, and 818 can include any configuration of electric fieldgenerating electrodes (i.e., supply electrodes) and electric fieldsensing electrodes. In some embodiments, internal electric lead 801 orexternal electric lead 802 can include both electric field generatingand electric field sensing electrodes in any configuration.

The proximal ends of internal electric lead 801 or external electriclead 802 are disposed within the housing 302. The distal ends ofinternal electric lead 801 can surround a cancerous tumor 310 such thatthe electrodes 804, 806, 808, and 810 are brought into proximity of thecancerous tumor 310. External electric lead 802 can be placed on theexterior of the subject's body near the site of the cancerous tumor suchthat the electrodes 812, 814, 816, and 818 are in electricalcommunication with electrodes 804, 806, 808, and 810 on internalelectric lead 801. In some embodiments, the internal electric lead 801can be positioned within the vasculature such that electrodes 804, 806,808, and 810 are adjacent to or positioned within the cancerous tumor310. However, it will be appreciated that internal electric lead 801 canbe disposed in various places within or around the cancerous tumor 310.In some embodiments, the internal electric lead 801 can pass directlythrough the cancerous tumor 310.

In some embodiments, the internal electric lead 801 can include one ormore tracking markers 826 along the length of the internal electric lead801 for use in determining the precise location of the electrodesrelative to the tumor. In some embodiments, the one or more trackingmarkers can be disposed directly distal or directly proximal to the oneor more electrodes disposed on the internal electric lead 801. In someembodiments, the tracking markers can be formed from a magneticmaterial. In some embodiments, the tracking markers can be formed from aradiographic material. In some embodiments, the tracking markers can beformed from a fluorographic material.

It will be appreciated that a plurality of electric field vectors can begenerated between various combinations of supply electrodes 806, 810,814, or 818 disposed along internal electric lead 801 and externalelectric lead 802 to create an electric field. For example, one or moreelectric field vectors can be generated between supply electrodes 806and 814. Similarly, one or more electric field vectors can be generatedbetween supply electrodes 810 and 818. It will also be appreciated thatone or more electric field vectors can be generated between anycombination of supply electrodes 806, 810, 814, or 818. In someembodiments, one or more electric field vectors can be generated betweenany combination of supply electrodes 806, 810, 814, or 818 and thehousing 302 of medical device 800.

It will be appreciated that sensing electrodes 804, 808, 812, and 816can sense an impedance 524 within the cancerous tumor 310 along one ormore vectors between any combination of sensing electrodes 804, 808,812, and 816, where sensing an impedance 524 of a cancerous tumor can beindependent of any impedance present in any of supply electrodes 806,810, 814, or 818 or any wires or components in electrical communicationtherewith. Each sensing electrode can be configured to measure impedanceof the cancerous tumor 310 independent of an impedance produced by anyof the supply electrodes, leads, wires and any components in electricalcommunication therewith.

It will be appreciated that sensing electrodes 804, 808, 812, and 816can sense an impedance 824 of any of the supply electrodes along one ormore vectors between any combination of sensing electrodes 804, 808,812, and 816 and the supply electrodes 806, 810, 814, or 818. In someembodiments, the electrodes 804, 808, 812, and 816 can be sensingelectrodes that can sense an impedance 824 of any of the supplyelectrodes along one or more non-therapy vectors. Each sensing electrodecan be further configured to measure impedance of any of the electrodes806, 810, 814, or 818, which can be supply electrodes, where themeasured impedance is independent of an impedance produced by any of theother supply electrodes, leads, wires and any components in electricalcommunication therewith. In some embodiments, the supply electrodes 806,810, 814, or 818 can perform unipolar impedance measurements todifferentiate the impedance of each supply electrode. A “unipolar”impedance measurement refers to the scenario where the housing (or caseor can) of the implanted device itself serves as one of the twoelectrodes in the pair required for passing a current in order tomeasure voltage drop and derive impedance. A “bipolar” impedancemeasurement refers to the scenario where the housing (or case or can) ofthe implanted device itself does not serve as one of the two electrodesin the pair required for passing a current in order to measure voltagedrop and derive impedance (e.g., the two electrodes are disposed onleads or other structures external to the housing of implanted device).In some embodiments, the various impedance measurements herein can beunipolar impedance measurements, while in other embodiments the variousimpedance measurements herein can be bipolar impedance measurements.

The medical devices described herein for treating a cancerous tumor canalso include one or more sensing electrodes that can be configured tomeasure an impedance of one or more supply electrodes to monitor thequality of the electrode during a given therapy. Referring now to FIG.9, a medical device 900 is shown in accordance with the embodimentsherein. Medical device 900 can include an electric field generatingcircuit configured to generate one or more electric fields at or nearthe site of a cancerous tumor 310. The medical device 900 can includecontrol circuitry in communication with the electric field generatingcircuit, the control circuitry configured to control delivery of the oneor more electric fields from the electric field generating circuit. Thecontrol circuitry can cause the electric field generating circuit togenerate one or more electric fields at frequencies selected from arange of between 10 kHz to 1 MHz at or near a site of the canceroustumor.

The medical device 900 can include one or more supply leads inelectrical communication with the electric field generating circuit, theone or more supply leads can each include one or more supply electrodesin electrical communication with the electric field generating circuit.The medical device 900 can also include one or more sensing leads inelectrical communication with the control circuitry, the one or moresensing leads can each one or more sensing electrodes. In someembodiments, the leads herein can include a combination lead that canserve either as a supply lead to provide an electric field at or nearthe site of a cancerous tumor, a sensing lead to measure an impedance ofeither a cancerous tumor, a healthy tissue, or a supply electrode, orboth a supply and sensing lead where indicated.

Medical device 900 includes first lead 902, second lead 908, third lead922, and fourth lead 928. The first lead 902 of medical device 900 caninclude a first electrode 914 in electrical communication with a firstwire 904 and a second electrode 916 in electrical communication with asecond wire 906. The second lead 908 of medical device 900 can include athird electrode 918 in electrical communication with the third wire 910and a fourth electrode 920 in electrical communication with the fourthwire 912. The first electrode 914 and the third electrode 918 can beconfigured as supply electrodes to form a supply electrode pair that candeliver an electric field at or near a site of the cancerous tumor 310.The second electrode 916 and the fourth electrode 920 can be configuredas sensing electrodes to form a sensing electrode pair configured tomeasure an impedance 524 of the cancerous tumor 310 independent of animpedance of a circuit formed by the first electrode 914, the first wire904, the third electrode 918, the third wire 910, and any components inelectrical communication therewith. The second electrode 916 and thefourth electrode 920 can be configured as sensing electrodes that canindividually, or together as a pair, measure an impedance 824 of any ofthe supply electrodes 914 or 918, where an impedance 824 of any of thesupply electrodes is independent of an impedance of a circuit formed bythe first electrode 914, the first wire 904, the third electrode 918,the third wire 910, and any components in electrical communicationtherewith.

The third lead 922 can include a fifth electrode 926 in electricalcommunication with a fifth wire 924, and the fourth lead 928 can includea sixth electrode 932 in electrical communication with a fifth wire 930.The fifth electrode 926 and the sixth electrode 932 can be configured assensing electrodes that form a sensing electrode pair configured tomeasure an impedance 524 of the cancerous tumor, where impedance 524 isindependent of an impedance of a circuit formed by the first electrode914, the first wire 904, the third electrode 918, the third wire 910,and any components in electrical communication therewith. The fifthelectrode 926 and the sixth electrode 932 can be configured as sensingelectrodes to measure impedance 824 of the one or more supplyelectrodes, where impedance 824 of any of the supply electrodes isindependent of an impedance of a circuit formed by the first electrode914, the first wire 904, the third electrode 918, the third wire 910,and any components in electrical communication therewith. In someembodiments, the sensing electrodes 926 and 932 can perform unipolarimpedance measurements to differentiate the impedance of each supplyelectrode.

In some embodiments, an increase in the impedance of one or more supplyelectrodes can indicate a broken or failing electrode. In someembodiments, if a supply electrode is determined to be broken orfailing, the housing 302 of medical device 900 can be used as a supplyelectrode. The housing 302 can include a portion that is in electricalcommunication with the electric field generating circuit, such that thehousing 302 can serve as a supply electrode. The one or more electricfields can be delivered along at least one vector including a portion ofthe housing serving as a supply electrode.

It will be appreciated that medical device 900 can include an electricfield generating circuit configured to generate one or more electricfields along a first vector, wherein the first vector can include anon-therapy vector. The medical device 900 can also include controlcircuitry in communication with the electric field generating circuit,where the control circuitry is configured to control delivery of one ormore electric fields from the electric field generating circuit.Electric field generating circuits and control circuitry will bediscussed in more detail elsewhere herein. The control circuitry cancause the electric field generating circuit to generate one or moreelectric fields at frequencies selected from a range of between 10 kHzto 1 MHz at a site of the cancerous tumor.

One or more supply leads of medical device 900 can be in electricalcommunication with the electric field generating circuit, where the oneor more supply leads each can each include one or more supply electrodesin electrical communication with the electric field generating circuit.One or more sensing leads of medical device 900 can be in electricalcommunication with the control circuitry, where the one or more sensingleads can each include one or more sensing electrodes. The one or moresensing electrodes can be configured to measure an impedance change inthe one or more supply electrodes along a second vector that isdifferent than the first vector along which the one or more electricfields are delivered to the cancerous tumor. In some embodiments, theone or more sensing electrodes of medical device 900 can be configuredto measure an impedance change in the cancerous tumor along a secondvector that is different than the first vector along which the one ormore electric fields are delivered to the cancerous tumor.

In some embodiments, the medical device 900 can include a housing 302 inwhich the electric field generating circuit and the control circuitryare disposed, where the housing includes a portion that is in electricalcommunication with the electric field generating circuit to serve as asupply electrode. The one or more electric fields can be delivered alongat least one vector including a portion of the housing serving as asupply electrode. In some embodiments of medical device 900, one or moresensing electrodes can be configured to perform unipolar impedancemeasurements to differentiate the impedance of each supply electrode. Insome embodiments of medical device 900, each supply electrode and eachsensing electrode is spatially separated along a longitudinal axis ofthe one or more leads by at least 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.5,0.75, 1, 2, 3, 4, 5, or 10 cm (or by an amount falling within a rangebetween any of the foregoing).

In some embodiments, the electrodes described herein can be spatiallyseparated along a longitudinal axis of the leads described herein by adistance that can be greater than or equal 1 mm, 5 mm, 10 mm, 15 mm, 20mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, or 100 mm, 150 mm, 200 mm, or 250mm. In some embodiments, the electrodes herein can be spatiallyseparated in more than one dimension from neighboring electrodes by adistance that can be greater than or equal 1 mm, 5 mm, 10 mm, 15 mm, 20mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, or 100 mm, 150 mm, 200 mm, or 250mm.

In some embodiments of medical device 900, measuring an impedance changein one or more supply electrodes along a second vector comprisesmeasuring the impedance change along a second vector that is spatiallyseparate from the first vector along which the one or more electricfields are delivered to the cancerous tumor by at least 30 degrees, byat least 60 degrees, or by at least 90 degrees. In some embodiments, thefirst vector and second vector can be spatially separated (e.g., thevectors can be disposed at an angle with respect to one another) by atleast about 10, 20, 30, 40, 50, 60, 70, 80 or 90 degrees. It will beappreciated that the supply electrode pair can deliver an electric fieldat or near the site of a cancerous tumor along multiple vectors, andthat the sensing electrode pair can similarly measure impedance alongmultiple vectors that are spatially separate from the vector used todeliver the electric field.

The various medical devices herein can include additional components inone or more configurations. The medical devices can include an electricfield generating circuit configured to generate one or more electricfields at or near the site of the cancerous tumor. The leads of themedical devices, such as a first lead, a second lead, a third lead, afourth lead, etc., can each be in electrical communication with theelectric field generating circuit. The medical devices can also includecontrol circuitry in communication with the electric field generatingcircuit, where the control circuitry can be configured to controldelivery of one or more electric fields from the electric fieldgenerating circuit. The control circuitry can cause the electric fieldgenerating circuit to generate one or more electric fields atfrequencies selected from a range of between 10 kHz to 1 MHz at or nearthe site of the cancerous tumor located within a bodily tissue. Theelectric field generating circuit and the control circuitry can bedisposed within housing 302. In some embodiments, the electric fieldgenerating circuit and the control circuitry are disposed within housing302.

In some embodiments, the various medical devices herein can deliver oneor more electric fields to the cancerous tumor at frequencies selectedfrom a range of from 10 kHz to 1 MHz. In some embodiments, the variousmedical devices herein can deliver one or more electric fields to thecancerous tumor at frequencies selected from a range of from 300 kHz to500 kHz. In some embodiments, the various medical devices herein candeliver one or more electric fields to the cancerous tumor atfrequencies selected from a range of from 100 kHz to 300 kHz. In someembodiments, the various medical devices herein can deliver one or moreelectric fields having an electric field strength selected from a rangeof electric field strengths from 0.25 V/cm to 1000 V/cm. In someembodiments, the various medical devices herein can deliver one or moreelectric fields having an electric field strength selected from a rangeof electric field strengths from 1 V/cm to 10 V/cm. In some embodiments,the various medical devices herein can deliver one or more electricfields having an electric field strength selected from a range ofelectric field strengths from 2 V/cm to 5 V/cm. Additional properties ofsuitable electric fields for delivery by the various medical devicesherein will be discussed in more detail below.

It will be appreciated that the embodiments shown herein include thosewith leads having wires and electrodes disposed along the longitudinalaxis, other medical devices can also include electrodes for generatingan electric field at or near the site of a cancerous tumor. In someembodiments, the wires and respective electrodes herein can be disposedon a device substrate. In some embodiments the device substrate caninclude a rigid body, a stent body, a blunt dissection probe, and thelike.

Referring now to FIG. 10, a schematic cross-sectional view of exemplarymedical device 1000 is shown in accordance with embodiments herein. Itwill be appreciated the features of medical device 1000 can be includedin any of the medical devices described herein. Housing 1002 can definean interior volume 1003 that can be hollow and that in some embodimentsis hermetically sealed off from the area 1005 outside of medical device1000. In other embodiments the housing 1002 can be filled withcomponents and/or structural materials such that it is non-hollow. Themedical device 1000 can include control circuitry 1006, which caninclude various components 1008, 1010, 1012, 1014, 1016, and 1018disposed within housing 1002. In some embodiments, these components canbe integrated and in other embodiments these components can be separate.In yet other embodiments, there can be a combination of both integratedand separate components. The medical device 1000 can also include anantenna 1024, to allow for unidirectional or bidirectional wireless datacommunication. In some embodiments, the components of medical device1000 can include an inductive energy receiver coil (not shown)communicatively coupled or attached thereto to facilitate transcutaneousrecharging of the medical device via recharging circuitry.

The various components 1008, 1010, 1012, 1014, 1016, and 1018 of controlcircuitry 1006 can include, but are not limited to, a microprocessor,memory circuit (such as random access memory (RAM) and/or read onlymemory (ROM)), recorder circuitry, controller circuit, a telemetrycircuit, a power supply circuit (such as a battery), a timing circuit,and an application specific integrated circuit (ASIC), a rechargingcircuit, amongst others. Control circuitry 1006 can be in communicationwith an electric field generating circuit 1020 that can be configured togenerate electric current to create one or more fields. The electricfield generating circuit 1020 can be integrated with the controlcircuitry 1006 or can be a separate component from control circuitry1006. Control circuitry 1006 can be configured to control delivery ofelectric current from the electric field generating circuit 1020. Insome embodiments, the electric field generating circuit 1020 can bepresent in a portion of the medical device that is external to the body.

In some embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to deliver an electricfield using one or more frequencies selected from a range of within 10kHz to 1 MHz. In some embodiments, the control circuitry 1006 can beconfigured to direct the electric field generating circuit 1020 todeliver an electric field at one or more frequencies selected from arange of within 300 kHz to 500 kHz. In some embodiments, the controlcircuitry 1006 can be configured to direct the electric field generatingcircuit 1020 to deliver an electric field at one or more frequenciesselected from a range of within 100 kHz to 300 kHz. In some embodiments,the control circuitry 1006 can be configured to direct the electricfield generating circuit 1020 to periodically deliver an electric fieldusing one or more frequencies greater than 1 MHz.

In some embodiments, the electric field can be effective in disruptingcellular mitosis in cancerous cells. The electric field can be deliveredto the site of a cancerous tumor along more than one vector. In someexamples, the electric field can be delivered along at least one vector,including at least one of the lead electrodes. In some embodiments, atleast two vectors with spatial diversity between the two vectors can beused. The vectors can be spatially separated (e.g., the vectors can bedisposed at an angle with respect to one another) by at least about 10,20, 30, 40, 50, 60, 70, 80 or 90 degrees.

A desired electric field strength can be achieved by delivering anelectric current between two electrodes. The specific current andvoltage at which the electric field is delivered can vary and can beadjusted to achieve the desired electric field strength at the site ofthe tissue to be treated. In some embodiments, the control circuitry1006 can be configured to direct the electric field generating circuit1020 to deliver an electric field using currents ranging from 1 mAmp to1000 mAmp to the site of a cancerous tumor. In some embodiments, thecontrol circuitry 1006 can be configured to direct the electric fieldgenerating circuit 1020 to deliver an electric field using currentsranging from 20 mAmp to 500 mAmp to the site of a cancerous tumor. Insome embodiments, the control circuitry 1006 can be configured to directthe electric field generating circuit 1020 to deliver an electric fieldusing currents ranging from 30 mAmp to 300 mAmp to the site of acancerous tumor.

In some embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to deliver an electricfield using currents including 1 mAmp, 2 mAmp, 3 mAmp, 4 mAmp, 5 mAmp, 6mAmp, 7 mAmp, 8 mAmp, 9 mAmp, 10 mAmp, 15 mAmp, 20 mAmp, 25 mAmp, 30mAmp, 35 mAmp, 40 mAmp, 45 mAmp, 50 mAmp, 60 mAmp, 70 mAmp, 80 mAmp, 90mAmp, 300 mAmp, 125 mAmp, 150 mAmp, 175 mAmp, 400 mAmp, 225 mAmp, 250mAmp, 275 mAmp, 300 mAmp, 325 mAmp, 350 mAmp, 375 mAmp, 400 mAmp, 425mAmp, 450 mAmp, 475 mAmp, 500 mAmp, 525 mAmp, 550 mAmp, 575 mAmp, 600mAmp, 625 mAmp, 650 mAmp, 675 mAmp, 700 mAmp, 725 mAmp, 750 mAmp, 775mAmp, 800 mAmp, 825 mAmp, 850 mAmp, 875 mAmp, 900 mAmp, 925 mAmp, 950mAmp, 975 mAmp, or 1000 mAmp. It will be appreciated that the controlcircuitry can be configured to direct the electric field generatingcircuit 1020 to deliver an electric field at a current falling within arange, wherein any of the forgoing currents can serve as the lower orupper bound of the range, provided that the lower bound of the range isa value less than the upper bound of the range.

In some embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to deliver an electricfield using voltages ranging from 1 V_(rms) to 50 V_(rms) to the site ofa cancerous tumor. In some embodiments, the control circuitry 1006 canbe configured to direct the electric field generating circuit 1020 todeliver an electric field using voltages ranging from 5 V_(rms) to 30V_(rms) to the site of a cancerous tumor. In some embodiments, thecontrol circuitry 1006 can be configured to direct the electric fieldgenerating circuit 1020 to deliver an electric field using voltagesranging from 10 V_(rms) to 20 V_(rms) to the site of a cancerous tumor.

In some embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to deliver an electricfield using one or more voltages including 1 V_(rms), 2 V_(rms), 3V_(rms), 4 V_(rms), 5 V_(rms), 6 V_(rms), 7 V_(rms), 8 V_(rms), 9V_(rms), 10 V_(rms), 15 V_(rms), 20 V_(rms), 25 V_(rms), 30 V_(rms), 35V_(rms), 40 V_(rms), 45 V_(rms), or 50 V_(rms). It will be appreciatedthat the control circuitry can be configured to direct the electricfield generating circuit 1020 to deliver an electric field using avoltage falling within a range, wherein any of the forgoing voltages canserve as the lower or upper bound of the range, provided that the lowerbound of the range is a value less than the upper bound of the range.

In some embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to deliver andelectric field using one or more frequencies including 10 kHz, 20 kHz,30 kHz, 40 kHz, 50 kHz, 60 kHz, 70 kHz, 80 kHz, 90 kHz, 300 kHz, 125kHz, 150 kHz, 175 kHz, 400 kHz, 225 kHz, 250 kHz, 275 kHz, 300 kHz, 325kHz, 350 kHz, 375 kHz, 400 kHz, 425 kHz, 450 kHz, 475 kHz, 500 kHz, 525kHz, 550 kHz, 575 kHz, 600 kHz, 625 kHz, 650 kHz, 675 kHz, 700 kHz, 725kHz, 750 kHz, 775 kHz, 800 kHz, 825 kHz, 850 kHz, 875 kHz, 900 kHz, 925kHz, 950 kHz, 975 kHz, 1 MHz. It will be appreciated that the electricfield generating circuit 1020 can deliver an electric field using afrequency falling within a range, wherein any of the foregoingfrequencies can serve as the upper or lower bound of the range, providedthat the upper bound is greater than the lower bound.

In some embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to generate one ormore applied electric field strengths selected from a range of within0.25 V/cm to 1000 V/cm. In some embodiments, the control circuitry 1006can be configured to direct the electric field generating circuit 1020to generate one or more applied electric field strengths of greater than3 V/cm. In some embodiments, the control circuitry 1006 can beconfigured to direct the electric field generating circuit 1020 togenerate one or more applied electric field strengths selected from arange of within 1 V/cm to 10 V/cm. In some embodiments, the controlcircuitry 1006 can be configured to direct the electric field generatingcircuit 1020 to generate one or more applied electric field strengthsselected from a range of within 2 V/cm to 5 V/cm.

In other embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to generate one ormore applied electric field strengths including 0.25 V/cm, 0.5 V/cm,0.75 V/cm, 1.0 V/cm, 2.0 V/cm, 3.0 V/cm, 5.0 V/cm, 6.0 V/cm, 7.0 V/cm,8.0 V/cm, 9.0 V/cm, 10.0 V/cm, 20.0 V/cm, 30.0 V/cm, 40.0 V/cm, 50.0V/cm, 60.0 V/cm, 70.0 V/cm, 80.0 V/cm, 90.0 V/cm, 300.0 V/cm, 125.0V/cm, 150.0 V/cm, 175.0 V/cm, 400.0 V/cm, 225.0 V/cm, 250.0 V/cm, 275.0V/cm, 300.0 V/cm, 325.0 V/cm, 350.0 V/cm, 375.0 V/cm, 400.0 V/cm, 425.0V/cm, 450.0 V/cm, 475.0 V/cm, 500.0 V/cm, 600.0 V/cm, 700.0 V/cm, 800.0V/cm, 900.0 V/cm, 1000.0 V/cm. It will be appreciated that the electricfield generating circuit 1020 can generate an electric field having afield strength at a treatment site falling within a range, wherein anyof the foregoing field strengths can serve as the upper or lower boundof the range, provided that the upper bound is greater than the lowerbound.

In some embodiments, the control circuitry 1006 can be configured todirect the electric field generating circuit 1020 to deliver an electricfield via leads 1007 to the site of a cancerous tumor located within abodily tissue. In other embodiments, the control circuitry 1006 can beconfigured to direct the electric field generating circuit 1020 todeliver an electric field via the housing 1002 of medical device 1000 tothe site of a cancerous tumor located within a bodily tissue. In otherembodiments, the control circuitry 1006 can be configured to direct theelectric field generating circuit 1020 to deliver an electric fieldbetween leads 1007 and the housing 1002 of medical device 1000. In someembodiments, one or more leads 1007 can be in electrical communicationwith the electric field generating circuit 1020. In some embodiments,the one or more leads 1007 can include one or more electrodes (not shownin FIG. 10) disposed along the length of the leads 1007, where theelectrodes can be in electrical communication with the electric fieldgenerating circuit 1020.

In some embodiments, various components within medical device 1000 caninclude an electric field sensing circuit 1022 configured to generate asignal corresponding to sensed electric fields. Electric field sensingcircuit 1022 can be integrated with control circuitry 1006 or it can beseparate from control circuitry 1006.

Sensing electrodes can be disposed on or adjacent to the housing of themedical device, on one or more leads connected to the housing, on aseparate device implanted near or in the tumor, or any combination ofthese locations. In some embodiments, the electric field sensing circuit1022 can include a first sensing electrode 1032 and a second sensingelectrode 1034. In other embodiments, the housing 1002 itself can serveas a sensing electrode for the electric field sensing circuit 1022. Thesensing electrodes 1032 and 1034 can be in communication with theelectric field sensing circuit 1022. The electric field sensing circuit1022 can measure the electrical potential difference (voltage) betweenthe first sensing electrode 1032 and the second sensing electrode 1034.In some embodiments, the electric field sensing circuit 1022 can measurethe electrical potential difference (voltage) between the first sensingelectrode 1032 or second sensing electrode 1034, and an electrodedisposed along the length of one or more leads 1007. In someembodiments, the electric field sensing circuit can be configured tomeasure sensed electric fields and to record electric field strength inV/cm.

It will be appreciated that the electric field sensing circuit 1022 canadditionally measure an electrical potential difference between thefirst sensing electrode 1032 or the second sensing electrode 1034 andthe housing 1002 itself. In other embodiments, the medical device caninclude a third electrode 1036, which can be an electric field sensingelectrode or an electric field generating electrode. In someembodiments, one or more sensing electrodes can be disposed along lead1007 and can serve as additional locations for sensing an electricfield. Many combinations can be imagined for measuring electricalpotential difference between electrodes disposed along the length of oneor more leads 1007 and the housing 1002 in accordance with theembodiments herein.

In some embodiments, the one or more leads 1007 can be in electricalcommunication with the electric field generating circuit 1020. The oneor more leads 1007 can include one or more electrodes disposed along alongitudinal axis or disposed at the tip of the lead. In someembodiments, various electrical conductors, such as electricalconductors 1026 and 1028, can pass from the header 1004 through afeed-through structure 1030 and into the interior volume 1003 of medicaldevice 1000. As such, the electrical conductors 1026 and 1028 can serveto provide electrical communication between the one or more leads 1007and control circuitry 1006 disposed within the interior volume 1003 ofthe housing 1002.

In some embodiments, recorder circuitry can be configured to record thedata produced by the electric field sensing circuit 1022 and record timestamps regarding the same. In some embodiments, the control circuitry1006 can be hardwired to execute various functions, while in otherembodiments the control circuitry 1006 can be directed to implementinstructions executing on a microprocessor or other external computationdevice. A telemetry circuit can also be provided for communicating withexternal computation devices such as a programmer, a home-based unit,and/or a mobile unit (e.g. a cellular phone, personal computer, smartphone, tablet computer, and the like).

Elements of various embodiments of the medical devices described hereinare shown in FIG. 11. However, it will be appreciated that someembodiments can include additional elements beyond those shown in FIG.11. In addition, some embodiments may lack some elements shown in FIG.11. The medical devices as embodied herein can gather informationthrough one or more sensing channels and can output information throughone or more field generating channels. A microprocessor 1102 cancommunicate with a memory 1104 via a bidirectional data bus. Themicroprocessor 1102 can be in electric communication with power supplycircuit 1120. The memory 1104 can include read only memory (ROM) orrandom access memory (RAM) for program storage and RAM for data storage.The microprocessor 1102 can also be connected to a telemetry interface1118 for communicating with external devices such as a programmer, ahome-based unit and/or a mobile unit (e.g. a cellular phone, personalcomputer, smart phone, tablet computer, and the like) or directly to thecloud or another communication network as facilitated by a cellular orother data communication network. In some embodiments, the medicaldevice can include an inductive energy receiver coil interface (notshown) communicatively coupled or attached thereto to facilitatetranscutaneous recharging of the medical device.

The medical device can include one or more electric field sensingelectrodes 1108 and one or more electric field sensor channel interfaces1106 that can communicate with a port of microprocessor 1102. Themedical device can also include one or more electric field generatingelectrodes 1112 and one or more electric field generating channelinterfaces 1110 and one or more electric field generating circuits 1109that can communicate with a port of microprocessor 1102. The medicaldevice can also include one or more other sensors 1116, such asphysiological sensors, respiration sensors, or chemical sensors, and oneor more other sensor channel interfaces 1114 that can communicate with aport of microprocessor 1102. The sensor channel interfaces 1106, 1110,and 1114 can include various components such as analog-to-digitalconverters for digitizing signal inputs, sensing amplifiers, registerswhich can be written to by the control circuitry in order to adjust thegain and threshold values for the sensing amplifiers, source drivers,modulators, demodulators, multiplexers, and the like.

In some embodiments, the physiological sensors can include sensors thatmonitor temperature, blood flow, blood pressure, and the like. In someembodiments, the respiration sensors can include sensors that monitorrespiration rate, respiration peak amplitude, and the like. In someembodiments, the chemical sensors can measure the quantity of an analytepresent in a treatment area about the sensor, including but not limitedto analytes such as of blood urea nitrogen, creatinine, fibrin,fibrinogen, immunoglobulins, deoxyribonucleic acids, ribonucleic acids,potassium, sodium, chloride, calcium, magnesium, lithium, hydronium,hydrogen phosphate, bicarbonate, and the like. However, many otheranalytes are also contemplated herein. Exemplary chemical/analytesensors are disclosed in commonly owned U.S. Pat. No. 7,809,441 to Kaneet al., and which is hereby incorporated by reference in its entirety.

Although the other sensors 1116 are shown as part of a medical device inFIG. 11, it is realized that in some embodiments one or more of theother sensors could be physically separate from the medical device. Invarious embodiments, one or more of the other sensors can be withinanother implanted medical device communicatively coupled to a medicaldevice via telemetry interface 1118. In yet other embodiments, one ormore of the other sensors can be external to the body and coupled to amedical device via telemetry interface 1118. In some embodiments, theother sensors can include drug delivery sensors, biopsy apparatussensors, optical sensors, or irrigation sensors.

Methods

Various methods are can be implemented with the devices describedherein. In some embodiments, a method of treating a cancerous tumor caninclude using four wire impedance measurements to direct therapy.Referring now to FIG. 12, a schematic view of an exemplary method 1200for treating a cancerous tumor is shown in accordance with theembodiments herein. Method 1200 includes implanting a first lead and asecond lead at or near a site of the cancerous tumor at 1202. The firstlead can include a first wire and a second wire, and the second lead caninclude a third wire and a fourth wire. The first wire can be inelectrical communication with a first electrode, the second wire can bein electrical communication with a second electrode, the third wire canbe in electrical communication with a third electrode, and the fourthwire can be in electrical communication with a fourth electrode. Thefirst electrode and the third electrode can form a first supplyelectrode pair configured to deliver an electric field at or near a siteof the cancerous tumor, and the second electrode and fourth electrodecan form a first sensing electrode pair configured to measure impedanceof the cancerous tumor independent of an impedance between the sensingelectrode pair. The method 1200 can include applying a therapeuticelectric field at or near a site of the cancerous tumor using the firstsupply electrode pair for a predetermined period of time at 1204. Themethod 1200 can include measuring the impedance of the cancerous tumorusing the first sensing electrode pair at 1206. In some embodiments, thefirst, second, third, and fourth wires and respective first, second,third, and fourth electrodes can be present on one lead or devicesubstrate. In some embodiments the device substrate can include a rigidbody, a stent body, a blunt dissection probe, and the like.

In some embodiments, the method 1200 can include measuring a change inthe impedance of the cancerous tumor by obtaining multiple measurementsover a predetermined amount of time. In some embodiments, the method1200 can include determining a regression of the cancerous tumor bydetecting an increase in the impedance over the predetermined period oftime. In some embodiments, the method 1200 can include determining aprogression of the cancerous tumor by detecting a decrease in theimpedance over the predetermined period of time. Without wishing to bebound by any particular theory, it is believed that a cancerous tumorincludes a greater amount of fluid, such as blood, lymph, and/orextracellular fluid within its structure as compared to healthysurrounding tissue. Since aqueous fluids are good conductors of current,an area with greater fluid volume, such as a cancerous tumor, willexhibit an impedance that is less than the impedance within a healthytissue. In some embodiments, the method 1200 can include adjusting thetherapeutic electric field if it is determined that a cancerous tumor isprogressing. In some embodiments, adjusting the therapeutic electricfield can include increasing the electric field strength, treatmentduration, frequency of the electric field, or combining an electricfield therapy with a chemotherapeutic agent.

Referring now to FIG. 13, a schematic view of an exemplary method 1300for treating a cancerous tumor is shown in accordance with theembodiments herein. The method 1300 can include implanting a first leadand a second lead at or near a site of the cancerous tumor at 1302. Thefirst lead and second lead can each include one or more supplyelectrodes and one or more sensing electrodes. The method 1300 caninclude applying an electric field at or near the site of the canceroustumor with the one or more supply electrodes for a predetermined periodof time at 1304. The method 1300 can include measuring the impedance ofeach supply electrode using one or more sensing electrode at 1306. Insome embodiments, the method 1300 can include performing unipolarimpedance measurements to differentiate the impedance of each supplyelectrode.

Referring now to FIG. 14, a schematic view of an exemplary method 1400for treating a cancerous tumor is shown in accordance with theembodiments herein. The method 1400 can include implanting a first lead,a second lead, a third lead, and a fourth lead at or near a site of thecancerous tumor at 1402. The first lead and third lead can each includeone or more supply electrodes, and the second lead and fourth lead caneach include one or more sensing electrodes. The method 1400 can includeapplying an electric field at or near the site of the cancerous tumorwith the supply electrodes for a predetermined period of time at 1404.The method 1400 can include measuring the impedance of each supplyelectrode using the one or more sensing electrodes. In some embodiments,the method 1400 can further include measuring the capacitance across thesupply electrodes, where the measured capacitance can be used todetermine the quality of the supply electrodes at 1406. In embodimentswhere it is determined that any of the supply electrodes is failing, useof the failing electrode can be discontinued.

Referring now to FIG. 15, a schematic view of an exemplary method 1500for treating a cancerous tumor is shown in accordance with theembodiments herein. The method 1500 can include implanting a first lead,a second lead, a third lead, and a fourth lead at or near a site of thecancerous tumor at 1502. The first lead and third lead can each includeone or more supply electrodes, and the second lead and fourth lead caneach include one or more sensing electrodes. The method 1500 can includeapplying an electric field at or near the site of the cancerous tumoralong a first vector with the one or more supply electrodes for apredetermined period of time at 1504. The method 1500 can includemeasuring the impedance of each supply electrode along a second vectorusing the one or more sensing electrodes at 1506. Measuring theimpedance of each supply electrode along a second vector can includemeasuring the impedance of each supply electrode along a second vectorthat is spatially separate from the first vector along which the one ormore electric fields are delivered to the cancerous tumor.

In some embodiments, the method 1500 can include performing unipolarimpedance measurements to differentiate the impedance of each supplyelectrode. In some embodiments, the method 1500 can include implantingany of the first lead, the second lead, the third lead, or the fourthlead at or near the site of the cancerous tumor through a natural bodyorifice or duct. The natural body orifice can be selected from any ofthe nasal passages, the ear canal, the mouth, the esophagus, thetrachea, the urethra, the vagina, the small intestine, the anus, or thecolon. The duct can be selected from any of the common bile duct, thebile duct, the pancreatic duct, the common hepatic duct, the ureters,the Eustachian tubes, or the fallopian tubes.

In the various methods described herein, applying the one or moreelectric fields can include at least applying an electric field atvarious electric field strengths. By way of example, the one or moreelectric fields can be applied to the cancerous tumor at electric fieldstrengths selected from a range of electric field strengths from 0.25V/cm to 1000 V/cm. In some embodiments, the one or more electric fieldscan be applied to the cancerous tumor at electric field strengthsselected from a range of electric field strengths from 1 V/cm to 10V/cm. In some embodiments, the one or more electric fields can beapplied to the cancerous tumor at electric field strengths selected froma range of electric field strengths from 2 V/cm to 5 V/cm. In someembodiments, the field strength can be greater than or equal to 0.25V/cm, 0.50 V/cm, 0.75 V/cm, 1.00 V/cm, 1.25 V/cm, 1.50 V/cm, 1.75 V/cm,2.00 V/cm, 2.25 V/cm, 2.50 V/cm, 2.75 V/cm, 3.00 V/cm, 3.25 V/cm, 3.50V/cm, 3.75 V/cm, 4.00 V/cm, 4.25 V/cm, 4.50 V/cm, 4.75 V/cm, 5.00 V/cm,5.25 V/cm, 5.50 V/cm, 5.75 V/cm, 6.00 V/cm, 6.25 V/cm, 6.50 V/cm, 6.75V/cm, 7.00 V/cm, 7.25 V/cm, 7.50 V/cm, 7.75 V/cm, 8.00 V/cm, 8.25 V/cm,8.50 V/cm, 8.75 V/cm, 9.00 V/cm, 9.25 V/cm, 9.50 V/cm, 9.75 V/cm, 10V/cm, 20 V/cm, 30 V/cm, 40 V/cm, 50 V/cm, 60 V/cm, 70 V/cm, 80 V/cm, 90V/cm, 300 V/cm, 150 V/cm, 400 V/cm, 250 V/cm, 300 V/cm, 350 V/cm, 400V/cm, 450 V/cm, 500 V/cm, 550 V/cm, 600 V/cm, 650 V/cm, 700 V/cm, 750V/cm, 800 V/cm, 850 V/cm, 900 V/cm, 950 V/cm, or 1000 V/cm, or can be anamount falling in a range within any of the foregoing.

In the various methods described herein, applying the one or moreelectric fields can include at least applying an electric field atvarious frequencies. The one or more electric fields can be applied tothe cancerous tumor at frequencies selected from a range within 10kilohertz (kHz) to 1 megahertz (MHz). In some embodiments, the one ormore electric fields can be applied to the cancerous tumor atfrequencies selected from a range within 300 kHz to 500 kHz. In someembodiments, the one or more electric fields can be applied to thecancerous tumor at frequencies selected from a range within 100 kHz to300 kHz. In some embodiments, the frequency of the one or more appliedelectric fields can be greater than or equal to 10 kHz, 20 kHz, 30 kHz,40 kHz, 50 kHz, 60 kHz, 70 kHz, 80 kHz, 90 kHz, 300 kHz, 125 kHz, 150kHz, 175 kHz, 400 kHz, 225 kHz, 250 kHz, 275 kHz, 300 kHz, 325 kHz, 350kHz, 375 kHz, 400 kHz, 425 kHz, 450 kHz, 475 kHz, 500 kHz, 525 kHz, 550kHz, 575 kHz, 600 kHz, 625 kHz, 650 kHz, 675 kHz, 700 kHz, 725 kHz, 750kHz, 775 kHz, 800 kHz, 825 kHz, 850 kHz, 875 kHz, 900 kHz, 925 kHz, 950kHz, 975 kHz, or 1 MHz or can be an amount falling in a range within anyof the foregoing.

In the various methods described herein, applying the one or moreelectric fields can include at least applying an electric field forvarious predetermined time periods. The one or more electric fields canbe applied at or near the site of the cancerous tumor over apredetermined time period selected from a range of predetermined timeperiods from 1 minute to 24 hours. In some embodiments, the one or moreelectric fields can be applied at or near the site of the canceroustumor over a predetermined time period can be greater than or equal to1, 10, 20, 30, 40, or 50 minutes, or 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0,4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0,11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0,17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0,23.5, 24.0, or 48 hours, or can be an amount falling in a range withinany of the foregoing.

In the various methods described herein, administering achemotherapeutic agent can include administering the chemotherapeuticagent for various predetermined time periods. The chemotherapeutic agentcan be administered at or near the site of the cancerous tumor over apredetermined time period selected from a range of predetermined timeperiods from less than 1 minute to 600 minutes. In some embodiments, thechemotherapeutic agent can be administered at or near the site of thecancerous tumor over a predetermined time period can be greater than orequal to 1 sec., 5 sec., 10 sec., 15 sec., 20 sec., 25 sec., 30 sec., 35sec., 40 sec., 45 sec., 50 sec., 55 sec., or 60 sec., 5 min., 10 min.,15 min., 20 min., 25 min., 30 min., 35 min., 40 min., 45 min., 50 min.,55 min., 60 min, 120 min, 180 min, 240 min, 300 min, 360 min, 420 min,480 min, 540 min, or 600 min, or can be an amount falling in a rangewithin any of the foregoing.

In the various methods described herein, applying the one or moreelectric fields at or near the site of the cancerous tumor can includeapplying the one or more electric fields to the exterior or interior ofthe subject. In some embodiments, applying the one or more electricfields to the cancerous tumor can include applying the one or moreelectric fields entirely to the exterior of the subject at or near thesite of the cancerous tumor. In some embodiments, applying the one ormore electric fields to the cancerous tumor can include applying the oneor more electric fields entirely to the interior of the subject at ornear the site of the cancerous tumor. In some embodiments, applying theone or more electric fields to the cancerous tumor can include applyingthe one or more electric fields at least partially to the exterior ofthe subject at or near the site of the cancerous tumor. In someembodiments, applying the one or more electric fields to the canceroustumor can include applying the one or more electric fields at leastpartially to the interior of the subject at or near the site of thecancerous tumor. In other embodiments, applying the one or more electricfields to the cancerous tumor can include applying the one or moreelectric fields partially to the interior and partially to the exteriorof the subject at or near the site of the cancerous tumor.

Impedance Measurements

Feedback obtained during electric field therapy can be used to monitorthe effectiveness of treating a cancerous tumor with the therapy. Datacan be measured for parameters such as impedance, capacitance, fieldstrength, etc. to direct a particular course of treatment. Without beingbound by any particular theory, it is believed that a cancerous tumorhas a particular impedance associated therewith. The impedanceassociated with a tumor can change as the size or cellular makeup of thetumor changes. Therefore, impedance can be monitored during the courseof an electric field therapy in order to determine if the canceroustumor is responding to therapy. In some instances, an increase inimpedance of the tissue in a treatment area including a cancerous tumorcan be indicative of tumor regression. In other instances, a decrease orno observed change in impedance of the tissue in a treatment area can beindicative of tumor progression or lack of change in the tumorrespectively. Other physiological properties associated with a canceroustumor, such as blood flow, metabolite concentrations, systemic cancermarkers, and temperature can also be used in conjunction with impedanceanalysis to monitor the progression or regression of a cancerous tumorin response to electric field therapy.

Ohm's law provides that electrical potential, current and impedance areinterrelated (V=IR or V=IZ). Thus, by knowing one variable (e.g., suchas a supplied current) and measuring another (e.g., such as measuringvoltage drop), the third variable can be calculated. In some embodimentsherein, impedance (Z) can be measured by taking the voltage and dividingby the current. Within the body, impedance can be influenced by a numberof factors, including but not limited to components in contact with anelectric field such as cell type, including muscle, fat, connectivetissue, and bone; cell density, cell size; electrolyte concentrations,etc. In some embodiments, electric field sensing or electric fieldgenerating electrodes can serve as impedance monitoring electrodes. Itwill be appreciated that different tissues will have differentimpedances at a given frequency. As such, in some embodiments, measuringimpedance at one or more frequencies at any given location iscontemplated. In some embodiments, impedance can be measured atfrequencies within the range of treatment frequencies. In someembodiments, impedance can be measured at frequencies outside oftreatment frequencies. In some embodiments, impedance can be measured atboth frequencies within the range of treatment frequencies andfrequencies outside of treatment frequencies.

In some embodiments, as impedance changes within a cancerous tumor,administering an electric field to the cancerous tumor can change basedon the measured impedance. Without being bound by any particular theory,it is believed that the impedance within a cancerous tumor is relativelylow when compared to non-cancerous or necrotic tissue. This phenomenonallows impedance to be monitored as a function of therapy duration andto serve as a diagnostic tool in assessing whether or not a tumor isresponding to an electric field therapy. If the impedance within atreatment area increases (across a fixed distance or area as a result ofthe low-impedance tumor tissue shrinking and non-cancerous tissueoccupying the remaining space) then this can be taken as an indicationthat the electric field therapy is effectively decreasing the size ofthe cancerous tumor. However, if the impedance within a treatment areadecreases or stays the same across a fixed distance or area then thiscan be taken as an indication that the electric field therapy is notdecreasing the size of the cancerous tumor. As such, electric fieldtherapies can be tailored to a particular cancerous tumor in order toeffectively decrease the size of the cancerous tumor. By way of example,one or more of the amplitude, frequency, pulse width, waveform,directionality, and/or duty cycle of the electric field therapy can bemodulated and/or changed.

In some embodiments, low-frequency impedance through a particularcancerous tumor can be used to measure conductivity through the tumorand can be used as an indicator of tissue progression or regression. Insome embodiments, high-frequency impedance through a particularcancerous tumor can be used to measure permittivity and capacitiveproperties of the tumor and can also be used as an indicator of tissueprogression or regression. In some embodiments, low-frequency impedancecan be measured at frequencies of about 1 Hz to about 10 Hz. In someembodiments, high-frequency impedance can be measured at frequencies ofabout 10 Hz to about 1 Mz. In some embodiments, high-frequency impedancecan be measured at frequencies of about 300 kHz to about 300 kHz. Invarious embodiments, a medical device including one or more componentsdescribed with respect to FIGS. 3 to 10 can be configured to execute oneor more operations described with respect to the methods embodied inFIGS. 12 to15.

Applied Electric Fields

The electric fields applied to the cancerous tumors using the methodsherein can be applied using a variety of modalities. Exemplarytherapeutic parameter sets can include those that implement thefollowing concepts: sweeping through a range of frequencies; stacking ofone or more frequencies simultaneously; stepping through one or morefrequencies sequentially; the spatial or temporal delivery of one ormore electric fields; sweeping through a range of electric fieldstrengths; applying an effective rotating electric field; modulating avoltage control mode or a current control mode; implementing one or moreduty cycles; pulse width modulation; manipulation of the electricalwaveform shape and/or pulse sequence; and the occasional use of highfrequency or high electric fields strength pulses.

The therapeutic parameter sets can be programmed into a medical deviceto operate autonomously, or they can be queried and manipulated by thesubject or a clinician using an external computation device such as aprogrammer, a home-based unit, and/or a mobile unit (e.g. a cellularphone, personal computer, smart phone, tablet computer, and the like).In other embodiments, the therapeutic parameter sets can be wirelesslycommunicated to the medical device from an external computation device.Frequencies and/or electric field strengths suitable for use in any ofthe therapeutic parameter sets herein are discussed above with respectto electric field generating circuit. In some embodiments, one or moretherapeutic parameter sets can be implemented simultaneously. In otherembodiments, one or more therapeutic parameter sets can be implementedin an alternating fashion. In some embodiments, the one or more electricfields can be effective to prevent and/or disrupt cellular mitosis in acancerous cell.

By way of example, an electric field can be applied to the site of acancerous tumor by sweeping through a range of frequencies. Referringnow to FIG. 16, exemplary plot 1602 shows an alternating electric field,where the frequency of the increases over time. Similarly, FIG. 17 showsthe change in frequency as a function of time in exemplary plot 1702during a programmed therapy parameter. In some embodiments, a frequencysweep can include sweeping from a minimum frequency up to a maximumfrequency. In some embodiments, a frequency sweep can include sweepingfrom a maximum frequency down to a minimum frequency. In otherembodiments, sweeping from a minimum frequency up to a maximum frequencyand sweeping from the maximum frequency down to the minimum frequencycan be repeated as many times as desired throughout the duration of thedelivery of the electric field from the electric field generatingcircuit.

As therapy progresses during a frequency sweep, it may be desired toalternate between frequency ranges so that as the cells within apopulation change in size and number in response to therapy, more cellscan be targeted. For example, in some embodiments, a frequency sweep caninclude alternating between a first frequency sweep covering a range ofabout 100 kHz to 300 kHz and a second frequency sweep covering a rangeabout 200 kHz to 500 kHz. It will be appreciated that sweeping through afirst and second frequency range as described can be performedindefinitely throughout the course of the therapy. In some embodiments,the second frequency sweep (range) can be at higher frequencies than thefirst frequency sweep (range). In some embodiments, the first frequencysweep (range) can be at higher frequencies than the second frequencysweep (range).

Frequency ranges for the first and second frequency ranges can be anyrange including specific frequencies recited above with respect toelectric field generating circuit, provided that the lower end of eachrange is a value less than the upper end of each range. At times, it maybe beneficial to have some amount of overlap between the frequency rangeof the first and second frequency sweep.

Leads and Electrodes

The leads described herein can be placed into the body at or near thesite of a cancerous tumor using a number of techniques. Placement of oneor more leads can include using techniques such as transvascularplacement, tunneling into the subcutaneous space, and/or surgicalplacement. In some embodiments, the placement of one or more leads caninclude placement via one or more natural body orifices. The medicaldevices herein can be configured for implanting any of the first lead,the second lead, the third lead, the fourth lead, etc., at or near thesite of the cancerous tumor through a natural body orifice or duct. Insome embodiments, the natural body orifice can include any of the nasalpassages, the ear canal, the mouth, the esophagus, the trachea, theurethra, the vagina, the small intestine, the anus, or the colon. Insome embodiment, a suitable duct can include those accessible via thegastrointestinal or genitourinary systems, including the common bileduct, the bile duct, the pancreatic duct, the common hepatic duct, theureters, the Eustachian tubes, or the fallopian tubes. The leads can beplaced adjacent to or within a cancerous tumor. In some embodiments,multiple leads can be used near to or far from the cancerous tumor.

In the medical devices described herein, it will be appreciated that oneor more unipolar or multipolar leads can be used in accordance with theembodiments herein. In some embodiments, a combination of unipolar andmultipolar leads can be used. In other embodiments, a circular lead,clamp lead, cuff lead, paddle lead, or patch lead can be used.

In some embodiments one or more leads described herein can be placed inthe subcutaneous space. Electrodes on leads placed in the subcutaneousspace can be used as the primary near-field generating electrode or as afar-field field generating electrode. In some embodiments, electrodes onleads placed in the subcutaneous space can be used as the primarynear-field generating electrode or as a far-field field generatingelectrode in conjunction with the housing of a medical device. Likewise,one or more leads can be placed transvascularly to act as far-fieldfield generating electrodes in conjunction with an electrode at or nearthe site of the cancerous tumor or in conjunction with the housing of amedical device.

The leads and electrodes described herein can include additionalfunctional and structural features. In some embodiments, the leads caninclude those that are compatible with imaging and treatment techniques,including but not limited to MRI (magnetic resonance imaging), X-rayimaging, deep brain stimulation techniques, and/or radiation therapy. Insome embodiments, the leads can include one or more conductor cores madefrom conducting materials. The conductor cores can be formed fromconducting materials including metals and/or other conducting materials.Metals can include, but are not limited to, palladium, platinum, silver,gold, copper, aluminum, various alloys including stainless steel,nickel-cobalt alloys such as MP35N® and the like. In some embodiments,the conductor core can be a multifilar coil, including but not limitedto a bifilar coil, a trifilar coil, and a quadfilar coil.

In some embodiments, electrodes can be disposed along the length of oneor more leads as described herein. Suitable materials for use in theelectrodes described herein can include metals such as palladium, tominimize coupling and artifact generation in magnetic fields. In someembodiments, electrodes can be made from other metals and/or otherconducting materials. Metals can include, but are not limited to,palladium, platinum, platinum alloys such as platinum-iridium alloy,gold, copper, tantalum, titanium, various alloys including stainlesssteel, and the like. In some embodiments, electrodes can be in the formof wound coils that can provide an added benefit of increased surfacearea without compromising flexibility of the electrodes. In someembodiments, the implantable device housing can serve as an electrode.

The leads described herein can also include one or more electrodesdisposed along the length of the lead. The leads can include two or moreelectrodes disposed along the length of the lead. In some embodiments,the electrodes can be tip electrodes found at the distal end of thelead. In other embodiments, the electrodes can be ring electrodes foundalong the lead but not at the tip of the lead.

In some embodiments, the electrodes can be coil electrodes. In someembodiments, a ring or tip electrode can be positioned in or adjacent toa tumor or cancerous tissue and a coil electrode can be positionedfarther from the tumor or cancerous tissue in order to help providespatial diversity to the generated electric fields. In some embodiments,one or more electrodes can have a length along the lengthwise axis(e.g., proximal to distal axis) of about 0.5, 1, 1.5, 2, 3, 4, 5, 7.5,10, 15, 20, 30, 40, 50, 75, 100 mm or more. In some embodiments, one ormore of the electrodes can have a length falling within a range whereinany of the foregoing distances can serve as the upper or lower bound ofthe range, provided that the upper bound is greater than the lowerbound.

The leads can be unipolar, bipolar, or multipolar. In some embodiments,a unipolar lead can include a lead that generates an electric fieldbetween one electrode and the housing of the medical device. In someembodiments, a bipolar lead can include a lead that can generate andelectric field between two electrodes disposed along the lead, orbetween both electrodes and the housing of the medical device. In someembodiments, a multipolar lead can include a lead that can generate anelectric field between the more than two electrodes disposed along thelead, between more than two electrodes and the housing of the medicaldevice, or any number of combinations of configurations of electrodesand the housing of the medical device.

The leads herein can include one or more optical emitters along thelength of the lead. Optical emitters suitable for use herein can includethose that emit light that falls anywhere along the visible spectrumfrom about 350 nm to 950 nm. Suitable optical emitters can include lightemitting diodes or laser diodes. Suitable LEDs can be made from one ormore of gallium arsenide (GaAs), gallium phosphide (GaP), galliumarsenide phosphide (GaAsP), silicon carbide (SiC) or fallium indiumnitride (GaInN). In some embodiments, the LEDs suitable for use hereincan include an LED capable of emitting only one color, or a mono-colorLED; an LED capable of emitting two colors, or a bi-color LED; an LEDcapable of emitting three colors, or a tri-color LED; or an LED capableof emitting more than three colors. The LEDs can be in electricalcommunication with control circuitry within the housing of the medicaldevices described herein. In some embodiments, one or more laser diodescan be included along the leads herein, and the laser diodes can be inoptical communication with one or more optical fibers disposed withinthe leads and used for transmitting light from a laser source to a laserdiode.

The electrodes suitable for use here can be made of conductive polymerssuch as carbon filled silicone, polyacetylene, polypyrrole, polyaniline,polytiophene, polyfuran, polyisoprene, polybutadiene, polyparaphenylene,and the like. In other embodiments, the electrodes can be insulated. Insome embodiments, the insulation surrounding and electrode can includemicroporous insulators to prevent cellular apposition, yet still allowfor current flow. Microporous insulators can be made from a number ofthe insulating materials described herein, including but not limited topolytetrafluoroethylene (ePTFE), polyethylene-co-tetrafluoroethene(ETFE), polyurethanes, silicones, poly(p-xylylene) polymers such asParylene polymers, polyether block amides such as PEBAX®, nylons, orderivatives thereof. In some embodiments, the electrodes can be coatedwith various materials, including but not limited to hydrogels orfractal coatings such as iridium oxide, titanium oxide, tantalumpentoxide, other metal oxides, poly(p-xylylene) polymers such asParylene, and the like.

A number of lead fixation techniques and configurations can be used inaccordance with the embodiments herein. Some non-limiting examples oflead fixation techniques can include biocompatible glue fixation, talonfixation, helix coil fixation, passive centering of the lead in thevascular system, tine fixation within the localized vascular system,spiral bias fixation within the localized vascular system, compressionfixation, suture sleeve fixation, and the like. In some examples, theleads embodied herein can be placed within the vascular systemsurrounding or adjacent to the site of the cancerous tumor. In otherembodiments, the leads embodied herein can be place surgically at orwithin or surrounding the site of the cancerous tumor.

The leads suitable for use herein can also include one or more openlumens that run the entire longitudinal length of, or a select portionof the longitudinal length of the lead. In some embodiments, the openlumen can include an integrated biopsy apparatus suitable for obtainingbiopsy samples from a cancerous tumor site on a periodic basis tomonitor disease progression and/or regression. Leads having an openlumen can also be configured to include an integrated drug deliverylumen that can deliver one or more drugs, such as steroids orchemotherapy agents, to the site of the tumor in a single bolus orperiodically via a metered pump. The leads can include one or moreportals disposed along the length of the lead to provide an outlet fordrug delivery at or near the site of a cancerous tumor.

In some embodiments a portion of the lead or the entire lead can includea drug eluting coating. In some embodiments, the drug eluting coatingcan include an anti-inflammatory agent, such as a steroid. In someembodiments, the steroid can be dexamethasone. In other embodiments, thedrug eluting coating can include a chemotherapy agent. In someembodiments, the chemotherapy agent can include a taxane or derivativesthereof, including but not limited to paclitaxel, docetaxel, and thelike. In other embodiments, the drug eluting coating can be configuredto release additional classes of chemotherapy agents, including, but notlimited to alkylating agents, plant alkaloids such as vinca alkaloids,cytotoxic antibiotics, topoisomerase inhibitors, and the like. In someembodiments, the drug eluting coating can be configured to release thedrug from the coating in a time-release fashion.

The leads herein can adopt a number of shapes or configurations. In someembodiments, the leads can be linear and in other embodiments the leadscan be circular. A circular lead may be a completely closed loop or itmay be a semi-closed loop. In some embodiments, the lead can include abendable core that can allow the lead to be shaped into manyconfigurations, including but not limited to a U shape, an S shape, aspiral shape, a half circle, an oval, and the like.

In yet other examples, the leads suitable for use herein can includefluorimetric or magnetic markers that can assist the clinician inprecise placement at or near the site of a cancerous tumor. The leadscan also include integrated pH sensors for detecting the change in thepH at or near the cancerous tumor or other chemical sensors suitable foranalyzing the concentration of a chemical analyte of interest.

Electric Field Generators

The medical devices embodied herein can include electric fieldgenerators particularly suited for therapeutic and diagnostic techniquesused during the course of treatment for a cancerous tumor. In someembodiments, the electric field generators suitable for use herein caninclude those that have been treated by radiation hardening to make thecomponents resistant to the damaging effects of radiation therapytreatments often prescribed as a main line treatment for canceroustumors. Electric field generators can include components such as thosedescribed in reference to FIGS. 3 and 5 above.

Electric field generators embodied herein can be programmed with anynumber of therapeutic parameter sets as described. The electric fieldgenerators can be programmed prior to implant, or they can be programmedby a clinician using an external computation device such as aprogrammer, a home-based unit, and/or a mobile unit (e.g. a cellularphone, personal computer, smart phone, tablet computer, and the like).In some embodiments, therapy parameters can be delivered to the electricfield generator via a telemetry circuit. In some embodiments, theelectric field generator can include a recharge circuit communicativelycoupled to a receiver coil to facilitate transcutaneous recharging ofthe medical device. In some embodiments, the electric field generatorcan communicate wirelessly between the receiver coil and an externalcharging device.

Further Embodiments

In an embodiment, a medical device for treating a cancerous tumor isincluded having a first lead can include a first wire and a second wire;a second lead can include a third wire and a fourth wire; a firstelectrode in electrical communication with the first wire, a secondelectrode in electrical communication with the second wire, a thirdelectrode in electrical communication with the third wire, and a fourthelectrode in electrical communication with the fourth wire; wherein thefirst electrode and the third electrode form a supply electrode pairconfigured to deliver one or more electric fields at or near a site ofthe cancerous tumor; and wherein the second electrode and the fourthelectrode form a sensing electrode pair configured to measure animpedance of the cancerous tumor independent of an impedance of thefirst electrode, the first wire, the third electrode, the third wire,and components in electrical communication therewith.

In an embodiment, the medical device can include an electric fieldgenerating circuit configured to generate the one or more electricfields.

In an embodiment, the first lead and the second lead are each inelectrical communication with the electric field generating circuit.

In an embodiment, the medical device can further include a controlcircuitry in communication with the electric field generating circuit,the control circuitry configured to control delivery of the one or moreelectric fields from the electric field generating circuit.

In an embodiment, the control circuitry causes the electric fieldgenerating circuit to generate one or more electric fields atfrequencies selected from a range of between 10 kHz to 1 MHz at or nearthe site of the cancerous tumor located within a bodily tissue.

In an embodiment, the medical device is configured to be implantedentirely within a subject.

In an embodiment, the medical device is configured to be partiallyimplanted within a subject.

In an embodiment, the one or more electric fields are delivered to thecancerous tumor at frequencies selected from a range of from 100 kHz to300 kHz.

In an embodiment, the first lead and the second lead are each inelectrical communication with the electric field generating circuit.

In an embodiment, the first wire, the second wire, the third wire, andthe fourth wire are electrically insulated from one another.

In an embodiment, a current flow through the second electrode, thesecond wire, the fourth electrode, the fourth wire, and components inelectrical communication therewith is negligible.

In an embodiment, a current flow through the second electrode, thesecond wire, the fourth electrode, the fourth wire, and components inelectrical communication therewith is less than 100 pA.

In an embodiment, the first electrode and the second electrode of thefirst lead are spatially separated along a longitudinal axis of thefirst lead by at least 1 mm; and wherein the third electrode and thefourth electrode of the second lead are spatially separated along alongitudinal axis of the second lead by at least 1 mm.

In an embodiment, the one or more electric fields are effective toprevent and/or disrupt cellular mitosis in a cancerous cell.

In an embodiment, the medical device is configured to be implantedentirely within a subject.

In an embodiment, the medical device is configured to be partiallyimplanted within a subject.

In an embodiment, the medical device is configured to be entirelyexternal to a subject.

In an embodiment, the one or more electric fields are delivered to thecancerous tumor at frequencies selected from a range of from 10 kHz to 1MHz.

In an embodiment, the one or more electric fields are applied to thecancerous tumor at frequencies selected from a range of from 100 kHz to500 kHz.

In an embodiment, the one or more electric fields are delivered to thecancerous tumor at frequencies selected from a range of from 100 kHz to300 kHz.

In an embodiment, the one or more electric fields include an electricfield strength selected from a range of electric field strengths from0.25 V/cm to 1000 V/cm.

In an embodiment, the one or more electric fields include an electricfield strength selected from a range of electric field strengths from 1V/cm to 10 V/cm.

In an embodiment, the one or more electric fields include an electricfield strength selected from a range of electric field strengths from 3V/cm to 5 V/cm.

In an embodiment, a medical device for treating a cancerous tumor isincluded having a first lead can include a first wire, a second lead caninclude a second wire, a third lead can include a third wire, and afourth lead can include a fourth wire; a first electrode in electricalcommunication with the first wire, a second electrode in electricalcommunication with the second wire, a third electrode in electricalcommunication with the third wire, and a fourth electrode in electricalcommunication with the fourth wire; wherein the first electrode and thethird electrode form a supply electrode pair configured to deliver anelectric field at or near a site of the cancerous tumor; and wherein thesecond electrode and the fourth electrode form a sensing electrode pairconfigured to measure impedance of the cancerous tumor independent of animpedance of the first electrode, the first wire, the third electrode,the third wire, and components in electrical communication therewith.

In an embodiment, the medical device can further include a fifthelectrode in electrical communication with a fifth wire, a sixthelectrode in electrical communication with a sixth wire, a seventhelectrode in electrical communication with a seventh wire, and an eighthelectrode in electrical communication with an eighth wire.

In an embodiment, a method for treating a cancerous tumor is included,the method including implanting a first lead and a second lead at ornear a site of the cancerous tumor, the first lead can include a firstwire and a second wire; and the second lead can include a third wire anda fourth wire; wherein the first wire is in electrical communicationwith a first electrode; the second wire is in electrical communicationwith a second electrode; the third wire is in electrical communicationwith a third electrode; and the fourth wire is in electricalcommunication with a fourth electrode; and wherein the first electrodeand the third electrode form a first supply electrode pair configured todeliver an electric field at or near a site of the cancerous tumor, andthe second electrode and fourth electrode form a first sensing electrodepair configured to measure impedance of the cancerous tumor independentof an impedance between the first sensing electrode pair applying atherapeutic electric field at or near a site of the cancerous tumorusing the first supply electrode pair for a predetermined period oftime; measuring the impedance of the cancerous tumor using the firstsensing electrode pair.

In an embodiment, the cancerous tumor can include a cancerous cellpopulation.

In an embodiment, a method can further include measuring an initialimpedance of the cancerous tumor prior to beginning treating thecancerous tumor, wherein measuring the initial impedance includesapplying a diagnostic electric field at or near the site of thecancerous tumor and recording the initial impedance.

In an embodiment, measuring the impedance of the cancerous tumorincludes obtaining multiple measurements over a predetermined amount oftime.

In an embodiment, a method can further include determining a regressionof the cancerous tumor by detecting an increase in the impedance overthe predetermined period of time.

In an embodiment, a method can further include determining a progressionof the cancerous tumor by detecting a decrease in the impedance over thepredetermined period of time.

In an embodiment, a method can further include adjusting the therapeuticelectric field.

In an embodiment, measuring the impedance of the cancerous tumorincludes obtaining multiple measurements over a predetermined amount oftime.

In an embodiment, a method can further include determining a regressionof the cancerous tumor by detecting an increase in the impedance overthe predetermined period of time.

In an embodiment, a method can further include determining a progressionof the cancerous tumor by detecting a decrease in the impedance over thepredetermined period of time.

In an embodiment, a method can further include adjusting the therapeuticelectric field.

In an embodiment, a medical device for treating a cancerous tumor isincluded having an electric field generating circuit configured togenerate one or more electric fields; control circuitry in communicationwith the electric field generating circuit, the control circuitryconfigured to control delivery of the one or more electric fields fromthe electric field generating circuit; wherein the control circuitrycauses the electric field generating circuit to generate one or moreelectric fields at frequencies selected from a range of between 10 kHzto 1 MHz at or near a site of the cancerous tumor; one or more supplyleads in electrical communication with the electric field generatingcircuit, the one or more supply leads each can include one or moresupply electrodes in electrical communication with the electric fieldgenerating circuit; and one or more sensing leads in electricalcommunication with the control circuitry, the one or more sensing leadseach can include one or more sensing electrodes; and wherein the one ormore sensing electrodes are configured to measure an impedance of theone or more supply electrodes.

In an embodiment, a medical device can further include a housing inwhich the electric field generating circuit and the control circuitryare disposed, wherein the housing includes a portion that is inelectrical communication with the electric field generating circuit suchthat the housing serves as a supply electrode, wherein the one or moreelectric fields are delivered along at least one vector including aportion of the housing serving as a supply electrode.

In an embodiment, the one or more sensing electrodes are configured toperform unipolar impedance measurements to differentiate the impedanceof each supply electrode.

In an embodiment, the one or more sensing electrodes are configured toperform unipolar impedance measurements to differentiate the impedanceof each supply electrode.

In an embodiment, a method for treating a cancerous tumor is included,the method including implanting a first lead and a second lead at ornear a site of the cancerous tumor; wherein the first lead and secondlead each include one or more supply electrodes and one or more sensingelectrodes; applying an electric field at or near the site of thecancerous tumor with the one or more supply electrodes for apredetermined period of time; measuring an impedance of each supplyelectrode using one or more sensing electrodes.

In an embodiment, a method can further include performing unipolarimpedance measurements to differentiate the impedance of each supplyelectrode.

In an embodiment, a method for treating a cancerous tumor is included,the method implanting a first lead, a second lead, a third lead, and afourth lead at or near a site of the cancerous tumor; wherein the firstlead and third lead each include one or more supply electrodes, and thesecond lead and fourth lead each include one or more sensing electrodes;applying an electric field at or near the site of the cancerous tumorwith the supply electrodes for a predetermined period of time; measuringan impedance of each supply electrode using the one or more sensingelectrodes.

In an embodiment, a method can further include measuring a capacitanceacross the supply electrodes; wherein the measured capacitance can beused to determine a quality of the supply electrodes.

In an embodiment, a medical device for treating a cancerous tumor isincluded having an electric field generating circuit configured togenerate one or more electric fields along a first vector; controlcircuitry in communication with the electric field generating circuit,the control circuitry configured to control delivery of the one or moreelectric fields from the electric field generating circuit; wherein thecontrol circuitry causes the electric field generating circuit togenerate one or more electric fields at frequencies selected from arange of between 10 kHz to 1 MHz at a site of the cancerous tumor; oneor more supply leads in electrical communication with the electric fieldgenerating circuit, the one or more supply leads each can include one ormore supply electrodes in electrical communication with the electricfield generating circuit; and one or more sensing leads in electricalcommunication with the control circuitry, the one or more sensing leadseach can include one or more sensing electrodes; and wherein the one ormore sensing electrodes are configured to measure an impedance change inthe one or more supply electrodes along a second vector that isdifferent than the first vector along which the one or more electricfields are delivered to the cancerous tumor.

In an embodiment, a device can further include a housing in which theelectric field generating circuit and the control circuitry aredisposed, wherein the housing includes a portion that is in electricalcommunication with the electric field generating circuit to serve as asupply electrode, wherein the one or more electric fields are deliveredalong at least one vector including a portion of the housing serving asa supply electrode.

In an embodiment, the one or more sensing electrodes are configured toperform unipolar impedance measurements to differentiate the impedanceof each supply electrode.

In an embodiment, measuring an impedance change in the one or moresupply electrodes along a second vector includes measuring the impedancechange along a second vector that is spatially separate from the firstvector along which the one or more electric fields are delivered to thecancerous tumor by at least 30 degrees.

In an embodiment, measuring an impedance change in the one or moresupply electrodes along a second vector includes measuring the impedancechange along a second vector that is spatially separate from the firstvector along which the one or more electric fields are delivered to thecancerous tumor by at least 60 degrees.

In an embodiment, measuring an impedance change in the one or moresupply electrodes along a second vector includes measuring the impedancechange along a second vector that is spatially separate from the firstvector along which the one or more electric fields are delivered to thecancerous tumor by at least 90 degrees.

In an embodiment, each supply electrode and each sensing electrode isspatially separated along a longitudinal axis of the one or more leadsby at least 0.25 cm.

In an embodiment, a medical device for treating a cancerous tumor isincluded having an electric field generating circuit configured togenerate one or more electric fields along a first vector; controlcircuitry in communication with the electric field generating circuit,the control circuitry configured to control delivery of the one or moreelectric fields from the electric field generating circuit; wherein thecontrol circuitry causes the electric field generating circuit togenerate one or more electric fields at frequencies selected from arange of between 10 kHz to 1 MHz at a site of the cancerous tumor; oneor more supply leads in electrical communication with the electric fieldgenerating circuit, the one or more supply leads each can include one ormore supply electrodes in electrical communication with the electricfield generating circuit; and one or more sensing leads in electricalcommunication with the control circuitry, the one or more sensing leadseach can include one or more sensing electrodes; and wherein the one ormore sensing electrodes are configured to measure an impedance change inthe cancerous tumor along a second vector that is different than thefirst vector along which the one or more electric fields are deliveredto the cancerous tumor.

In an embodiment, a method for treating a cancerous tumor is included,the method including implanting a first lead, a second lead, a thirdlead, and a fourth lead at or near a site of the cancerous tumor;wherein the first lead and third lead each include one or more supplyelectrodes, and the second lead and fourth lead each include one or moresensing electrodes; applying an electric field at or near the site ofthe cancerous tumor along a first vector with the one or more supplyelectrodes for a predetermined period of time; measuring the impedanceof each supply electrode along a second vector using the one or moresensing electrodes; and wherein measuring the impedance of each supplyelectrode along a second vector includes measuring the impedance of eachsupply electrode along a second vector that is spatially separate fromthe first vector along which the one or more electric fields aredelivered to the cancerous tumor.

In an embodiment, a method can further include performing unipolarimpedance measurements to differentiate the impedance of each supplyelectrode.

In an embodiment, implanting any of the first lead, the second lead, thethird lead, or the fourth lead at or near the site of the canceroustumor includes delivery of any of the first lead, the second lead, thethird lead, or the fourth lead through a natural body orifice or duct.

In an embodiment, the natural body orifice can be selected from any of anasal passage, an ear canal, a mouth, an esophagus, a trachea, aurethra, a vagina, a small intestine, an anus, or a colon.

In an embodiment, the duct can be selected from any of a common bileduct, a bile duct, a pancreatic duct, a common hepatic duct, a ureter, aEustachian tube, or a fallopian tube.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase “configured” describes a system, apparatus,or other structure that is constructed or configured to perform aparticular task or adopt a particular configuration. The phrase“configured” can be used interchangeably with other similar phrases suchas arranged and configured, constructed and arranged, constructed,manufactured and arranged, and the like.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference.

The embodiments described herein are not intended to be exhaustive or tolimit the invention to the precise forms disclosed in the followingdetailed description. Rather, the embodiments are chosen and describedso that others skilled in the art can appreciate and understand theprinciples and practices. As such, aspects have been described withreference to various specific and preferred embodiments and techniques.However, it should be understood that many variations and modificationsmay be made while remaining within the spirit and scope herein.

1. A medical device for treating a cancerous tumor comprising: a firstlead comprising a first wire and a second wire; a second lead comprisinga third wire and a fourth wire; a first electrode in electricalcommunication with the first wire, a second electrode in electricalcommunication with the second wire, a third electrode in electricalcommunication with the third wire, and a fourth electrode in electricalcommunication with the fourth wire; wherein the first electrode and thethird electrode form a supply electrode pair configured to deliver oneor more electric fields at or near a site of the cancerous tumor; andwherein the second electrode and the fourth electrode form a sensingelectrode pair configured to measure an impedance of the cancerous tumorindependent of an impedance of the first electrode, the first wire, thethird electrode, the third wire, and components in electricalcommunication therewith.
 2. The medical device of claim 1, furthercomprising an electric field generating circuit configured to generatethe one or more electric fields.
 3. The medical device of claim 2,wherein the first lead and the second lead are each in electricalcommunication with the electric field generating circuit.
 4. The medicaldevice of claim 2, further comprising a control circuitry incommunication with the electric field generating circuit, the controlcircuitry configured to control delivery of the one or more electricfields from the electric field generating circuit.
 5. The medical deviceof claim 4, wherein the control circuitry causes the electric fieldgenerating circuit to generate one or more electric fields atfrequencies selected from a range of between 10 kHz to 1 MHz at or nearthe site of the cancerous tumor located within a bodily tissue.
 6. Themedical device of claim 1, wherein the medical device is configured tobe implanted entirely within a subject.
 7. The medical device of claim1, wherein the medical device is configured to be partially implantedwithin a subject.
 8. The medical device of claim 1, wherein the one ormore electric fields are delivered to the cancerous tumor at frequenciesselected from a range of from 100 kHz to 300 kHz.
 9. The medical deviceof claim 1, wherein a current flow through the second electrode, thesecond wire, the fourth electrode, the fourth wire, and components inelectrical communication therewith is less than 100 pA.
 10. The medicaldevice of claim 1, wherein the first electrode and the second electrodeof the first lead are spatially separated along a longitudinal axis ofthe first lead by at least 1 mm; and wherein the third electrode and thefourth electrode of the second lead are spatially separated along alongitudinal axis of the second lead by at least 1 mm.
 11. The medicaldevice of claim 1, wherein the one or more electric fields comprise anelectric field strength selected from a range of electric fieldstrengths from 0.25 V/cm to 1000 V/cm.
 12. A method for treating acancerous tumor comprising: implanting a first lead and a second lead ator near a site of the cancerous tumor, the first lead comprising a firstwire and a second wire; and the second lead comprising a third wire anda fourth wire; wherein the first wire is in electrical communicationwith a first electrode; the second wire is in electrical communicationwith a second electrode; the third wire is in electrical communicationwith a third electrode; and the fourth wire is in electricalcommunication with a fourth electrode; and wherein the first electrodeand the third electrode form a first supply electrode pair configured todeliver an electric field at or near a site of the cancerous tumor, andthe second electrode and fourth electrode form a first sensing electrodepair configured to measure impedance of the cancerous tumor independentof an impedance between the first sensing electrode pair; applying atherapeutic electric field at or near a site of the cancerous tumorusing the first supply electrode pair for a predetermined period oftime; measuring the impedance of the cancerous tumor using the firstsensing electrode pair.
 13. The method of claim 12, further comprisingmeasuring an initial impedance of the cancerous tumor prior to beginningtreating the cancerous tumor, wherein measuring the initial impedancecomprises applying a diagnostic electric field at or near the site ofthe cancerous tumor and recording the initial impedance.
 14. The methodof claim 12, wherein measuring the impedance of the cancerous tumorcomprises obtaining multiple measurements over a predetermined amount oftime.
 15. The method of claim 12, further comprising determining aregression of the cancerous tumor by detecting an increase in theimpedance over the predetermined period of time.
 16. The method of claim12, further comprising determining a progression of the cancerous tumorby detecting a decrease in the impedance over the predetermined periodof time.
 17. The method of claim 16, further comprising adjusting thetherapeutic electric field.
 18. A medical device for treating acancerous tumor comprising: an electric field generating circuitconfigured to generate one or more electric fields; control circuitry incommunication with the electric field generating circuit, the controlcircuitry configured to control delivery of the one or more electricfields from the electric field generating circuit; wherein the controlcircuitry causes the electric field generating circuit to generate oneor more electric fields at frequencies selected from a range of between10 kHz to 1 MHz at or near a site of the cancerous tumor; one or moresupply leads in electrical communication with the electric fieldgenerating circuit, the one or more supply leads each comprising one ormore supply electrodes in electrical communication with the electricfield generating circuit; and one or more sensing leads in electricalcommunication with the control circuitry, the one or more sensing leadseach comprising one or more sensing electrodes; and wherein the one ormore sensing electrodes are configured to measure an impedance of theone or more supply electrodes.
 19. The medical device of claim 18,further comprising a housing in which the electric field generatingcircuit and the control circuitry are disposed, wherein the housingincludes a portion that is in electrical communication with the electricfield generating circuit such that the housing serves as a supplyelectrode, wherein the one or more electric fields are delivered alongat least one vector including a portion of the housing serving as asupply electrode.
 20. The medical device of claim 19, wherein the one ormore sensing electrodes are configured to perform unipolar impedancemeasurements to differentiate the impedance of each supply electrode.